Pick Topic
Review Topic
List Experts
Examine Expert
Save Expert
  Site Guide ··   
Parkinson Disease: HELP
Articles by Ted M. Dawson
Based on 85 articles published since 2010
(Why 85 articles?)
||||

Between 2010 and 2020, Ted M. Dawson wrote the following 85 articles about Parkinson Disease.
 
+ Citations + Abstracts
Pages: 1 · 2 · 3 · 4
1 Review PINK1 and Parkin mitochondrial quality control: a source of regional vulnerability in Parkinson's disease. 2020

Ge, Preston / Dawson, Valina L / Dawson, Ted M. ·Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Department of Neurology, Department of Physiology, Solomon H. Snyder Department of Neuroscience, Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, 733 North Broadway, Suite 731, Baltimore, MD, 21205, USA. · Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA, 70130, USA. · Diana Helis Henry Medical Research Foundation, New Orleans, LA, 70130, USA. · Present address: Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA. · Present address: Picower Institute for Learning and Memory, Cambridge, MA, 02139, USA. · Present address: Harvard-MIT MD/PhD Program, Harvard Medical School, Boston, MA, 02115, USA. · Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Department of Neurology, Department of Physiology, Solomon H. Snyder Department of Neuroscience, Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, 733 North Broadway, Suite 731, Baltimore, MD, 21205, USA. vdawson@jhmi.edu. · Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA, 70130, USA. vdawson@jhmi.edu. · Diana Helis Henry Medical Research Foundation, New Orleans, LA, 70130, USA. vdawson@jhmi.edu. · Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Department of Neurology, Department of Physiology, Solomon H. Snyder Department of Neuroscience, Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, 733 North Broadway, Suite 731, Baltimore, MD, 21205, USA. tdawson@jhmi.edu. · Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA, 70130, USA. tdawson@jhmi.edu. · Diana Helis Henry Medical Research Foundation, New Orleans, LA, 70130, USA. tdawson@jhmi.edu. ·Mol Neurodegener · Pubmed #32169097.

ABSTRACT: That certain cell types in the central nervous system are more likely to undergo neurodegeneration in Parkinson's disease is a widely appreciated but poorly understood phenomenon. Many vulnerable subpopulations, including dopamine neurons in the substantia nigra pars compacta, have a shared phenotype of large, widely distributed axonal networks, dense synaptic connections, and high basal levels of neural activity. These features come at substantial bioenergetic cost, suggesting that these neurons experience a high degree of mitochondrial stress. In such a context, mechanisms of mitochondrial quality control play an especially important role in maintaining neuronal survival. In this review, we focus on understanding the unique challenges faced by the mitochondria in neurons vulnerable to neurodegeneration in Parkinson's and summarize evidence that mitochondrial dysfunction contributes to disease pathogenesis and to cell death in these subpopulations. We then review mechanisms of mitochondrial quality control mediated by activation of PINK1 and Parkin, two genes that carry mutations associated with autosomal recessive Parkinson's disease. We conclude by pinpointing critical gaps in our knowledge of PINK1 and Parkin function, and propose that understanding the connection between the mechanisms of sporadic Parkinson's and defects in mitochondrial quality control will lead us to greater insights into the question of selective vulnerability.

2 Review Finding useful biomarkers for Parkinson's disease. 2018

Chen-Plotkin, Alice S / Albin, Roger / Alcalay, Roy / Babcock, Debra / Bajaj, Vikram / Bowman, Dubois / Buko, Alex / Cedarbaum, Jesse / Chelsky, Daniel / Cookson, Mark R / Dawson, Ted M / Dewey, Richard / Foroud, Tatiana / Frasier, Mark / German, Dwight / Gwinn, Katrina / Huang, Xuemei / Kopil, Catherine / Kremer, Thomas / Lasch, Shirley / Marek, Ken / Marto, Jarrod A / Merchant, Kalpana / Mollenhauer, Brit / Naito, Anna / Potashkin, Judith / Reimer, Alyssa / Rosenthal, Liana S / Saunders-Pullman, Rachel / Scherzer, Clemens R / Sherer, Todd / Singleton, Andrew / Sutherland, Margaret / Thiele, Ines / van der Brug, Marcel / Van Keuren-Jensen, Kendall / Vaillancourt, David / Walt, David / West, Andrew / Zhang, Jing. ·Department of Neurology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. chenplot@pennmedicine.upenn.edu. · Neurology Service and GRECC, VAAHS, Ann Arbor, MI 48105, USA. · Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA. · Department of Neurology, Columbia University Medical Center, New York, NY 10032, USA. · National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20824, USA. · Verily/Google Life Sciences, South San Francisco, CA 94080, USA. · Department of Biostatistics, Mailman School of Public Health, Columbia University, New York, NY 10032, USA. · Human Metabolome Technology-America, Boston, MA 02134, USA. · Biogen, Cambridge, MA 02142, USA. · Caprion Biosciences, Montreal, Quebec H2X 3Y7, Canada. · Cell Biology and Gene Expression Section, Laboratory of Neurogenetics, National Institute of Aging, National Institutes of Health, Bethesda, MD 20892, USA. · Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. · Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. · Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA. · The Michael J. Fox Foundation for Parkinson's Research, New York, NY 10163, USA. · Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. · Department of Neurology, Penn State University-Hershey Medical Center, Hershey, PA 17033, USA. · Pharmaceutical Research and Early Development, NORD Discovery and Translational Area, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., 4070 Basel, Switzerland. · Institute for Neurodegenerative Disorders, New Haven, CT 06510, USA. · Departments of Cancer Biology and Pathology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA. · Blais Proteomics Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA. · Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA. · Chaperone Therapeutics, Portland, OR 97229, USA. · Paracelsus-Elena-Klinik, 34128 Kassel, Germany. · University Medical Center, 37075 Goettingen, Germany. · Department of Cellular and Molecular Pharmacology, Chicago Medical School, Rosalind Franklin University of Medicine and Science, Chicago, IL 60064, USA. · Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA. · Department of Neurology, Mount Sinai Beth Israel, Icahn School of Medicine at Mount Sinai, New York, NY 10003, USA. · Center for Advanced Parkinson's Disease Research and Precision Neurology Program, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. · Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD 20892, USA. · Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Luxembourg, Luxembourg. · Genentech, San Francisco, CA 94080, USA. · Neurogenomics Division, Translational Genomics Research Institute, Phoenix, AZ 85004, USA. · Department of Applied Physiology, Biomedical Engineering, and Neurology, University of Florida, Gainesville, FL 32611, USA. · Department of Neurology, University of Alabama, Birmingham, AL 35233, USA. · Department of Pathology, University of Washington, Seattle, WA 98195, USA. ·Sci Transl Med · Pubmed #30111645.

ABSTRACT: The recent advent of an "ecosystem" of shared biofluid sample biorepositories and data sets will focus biomarker efforts in Parkinson's disease, boosting the therapeutic development pipeline and enabling translation with real-world impact.

3 Review Activation mechanisms of the E3 ubiquitin ligase parkin. 2017

Panicker, Nikhil / Dawson, Valina L / Dawson, Ted M. ·Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, U.S.A. · Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, U.S.A. · Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130-2685, U.S.A. · Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, U.S.A. · Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, U.S.A. · Diana Helis Henry Medical Research Foundation, New Orleans, LA 70130-2685, U.S.A. · Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, U.S.A. tdawson@jhmi.edu. ·Biochem J · Pubmed #28860335.

ABSTRACT: Monogenetic, familial forms of Parkinson's disease (PD) only account for 5-10% of the total number of PD cases, but analysis of the genes involved therein is invaluable to understanding PD-associated neurodegenerative signaling. One such gene,

4 Review Trumping neurodegeneration: Targeting common pathways regulated by autosomal recessive Parkinson's disease genes. 2017

Scott, Laura / Dawson, Valina L / Dawson, Ted M. ·Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Cellular and Molecular Medicine Program, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130-2685, USA. · Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Cellular and Molecular Medicine Program, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130-2685, USA. · Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Cellular and Molecular Medicine Program, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130-2685, USA. Electronic address: tdawson2@jhmi.edu. ·Exp Neurol · Pubmed #28445716.

ABSTRACT: Parkinson's disease (PD) is a neurodegenerative movement disorder characterized by the progressive loss of dopaminergic (DA) neurons. Most PD cases are sporadic; however, rare familial forms have been identified. Autosomal recessive PD (ARPD) results from mutations in Parkin, PINK1, DJ-1, and ATP13A2, while rare, atypical juvenile ARPD result from mutations in FBXO7, DNAJC6, SYNJ1, and PLA2G6. Studying these genes and their function has revealed mitochondrial quality control, protein degradation processes, and oxidative stress responses as common pathways underlying PD pathogenesis. Understanding how aberrancy in these common processes leads to neurodegeneration has provided the field with numerous targets that may be therapeutically relevant to the development of disease-modifying treatments.

5 Review Models of LRRK2-Associated Parkinson's Disease. 2017

Xiong, Yulan / Dawson, Ted M / Dawson, Valina L. ·Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. yulanxiong@ksu.edu. · Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. yulanxiong@ksu.edu. · Department of Anatomy and Physiology, Kansas State University College of Veterinary Medicine, Manhattan, KS, 66506, USA. yulanxiong@ksu.edu. · Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. vdawson@jhmi.edu. · Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. vdawson@jhmi.edu. · Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. vdawson@jhmi.edu. · Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. vdawson@jhmi.edu. · Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA, 70130-2685, USA. vdawson@jhmi.edu. · Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. tdawson@jhmi.edu. · Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. tdawson@jhmi.edu. · Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. tdawson@jhmi.edu. · Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA, 70130-2685, USA. tdawson@jhmi.edu. · Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. tdawson@jhmi.edu. ·Adv Neurobiol · Pubmed #28353284.

ABSTRACT: Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most common genetic causes of Parkinson's disease (PD) and also one of the strongest genetic risk factors in sporadic PD. The LRRK2 protein contains a GTPase and a kinase domain and several protein-protein interaction domains. Both in vitro and in vivo assays in different model systems have provided tremendous insights into the molecular mechanisms underlying LRRK2-induced dopaminergic neurodegeneration. Among all the model systems, animal models are crucial tools to study the pathogenesis of human disease. How do the animal models recapitulate LRRK2-induced dopaminergic neuronal loss in human PD? To answer this question, this review focuses on the discussion of the animal models of LRRK2-associated PD including genetic- and viral-based models.

6 Review LRRK2 pathobiology in Parkinson's disease. 2014

Martin, Ian / Kim, Jungwoo Wren / Dawson, Valina L / Dawson, Ted M. ·Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. ·J Neurochem · Pubmed #25251388.

ABSTRACT: Mutations in the catalytic Roc-COR and kinase domains of leucine-rich repeat kinase 2 (LRRK2) are a common cause of familial Parkinson's disease (PD). LRRK2 mutations cause PD with age-related penetrance and clinical features identical to late-onset sporadic PD. Biochemical studies support an increase in LRRK2 kinase activity and a decrease in GTPase activity for kinase domain and Roc-COR mutations, respectively. Strong evidence exists that LRRK2 toxicity is kinase dependent leading to extensive efforts to identify selective and brain-permeable LRRK2 kinase inhibitors for clinical development. Cell and animal models of PD indicate that LRRK2 mutations affect vesicular trafficking, autophagy, protein synthesis, and cytoskeletal function. Although some of these biological functions are affected consistently by most disease-linked mutations, others are not and it remains currently unclear how mutations that produce variable effects on LRRK2 biochemistry and function all commonly result in the degeneration and death of dopamine neurons. LRRK2 is typically present in Lewy bodies and its toxicity in mammalian models appears to be dependent on the presence of α-synuclein, which is elevated in human iPS-derived dopamine neurons from patients harboring LRRK2 mutations. Here, we summarize biochemical and functional studies of LRRK2 and its mutations and focus on aberrant vesicular trafficking and protein synthesis as two leading mechanisms underlying LRRK2-linked disease.

7 Review Parkin and PINK1: much more than mitophagy. 2014

Scarffe, Leslie A / Stevens, Daniel A / Dawson, Valina L / Dawson, Ted M. ·Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130-2685, USA. · Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. · Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130-2685, USA. Electronic address: vdawson@jhmi.edu. · Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130-2685, USA. Electronic address: tdawson@jhmi.edu. ·Trends Neurosci · Pubmed #24735649.

ABSTRACT: Parkinson's disease (PD) is a progressive neurodegenerative disease that causes a debilitating movement disorder. Although most cases of PD appear to be sporadic, rare Mendelian forms have provided tremendous insight into disease pathogenesis. Accumulating evidence suggests that impaired mitochondria underpin PD pathology. In support of this theory, data from multiple PD models have linked Phosphatase and tensin homolog (PTEN)-induced putative kinase 1 (PINK1) and parkin, two recessive PD genes, in a common pathway impacting mitochondrial health, prompting a flurry of research to identify their mitochondrial targets. Recent work has focused on the role of PINK1 and parkin in mediating mitochondrial autophagy (mitophagy); however, emerging evidence casts parkin and PINK1 as key players in multiple domains of mitochondrial health and quality control.

8 Review Parkin plays a role in sporadic Parkinson's disease. 2014

Dawson, Ted M / Dawson, Valina L. ·Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, Md., USA. ·Neurodegener Dis · Pubmed #24029689.

ABSTRACT: BACKGROUND: Parkinson's disease (PD) is a chronic progressive neurologic disorder, which affects approximately one million men and women in the US alone. PD represents a heterogeneous disorder with common clinical manifestations and, for the most part, common neuropathological findings. OBJECTIVE: This short article reviews the role of the ubiquitin E3 ligase in sporadic PD. METHODS: The role of parkin in sporadic PD was reviewed by querying PubMed. RESULTS: Parkin is inactivated in sporadic PD via S-nitrosylation, oxidative and dopaminergic stress, and phosphorylation by the stress-activated kinase c-Abl, leading to the accumulation of AIMP2 and PARIS (ZNF746). CONCLUSION: Strategies aimed at maintaining parkin in a catalytically active state or interfering with the toxicity of AIMP2 and PARIS (ZNF746) offer new therapeutic opportunities.

9 Review Linked clinical trials--the development of new clinical learning studies in Parkinson's disease using screening of multiple prospective new treatments. 2013

Brundin, Patrik / Barker, Roger A / Conn, P Jeffrey / Dawson, Ted M / Kieburtz, Karl / Lees, Andrew J / Schwarzschild, Michael A / Tanner, Caroline M / Isaacs, Tom / Duffen, Joy / Matthews, Helen / Wyse, Richard K H. ·Center for Neurodegenerative Science, Van Andel Institute, MI, USA. ·J Parkinsons Dis · Pubmed #24018336.

ABSTRACT: Finding new therapies for Parkinson's disease (PD) is a slow process. We assembled an international committee of experts to examine drugs potentially suitable for repurposing to modify PD progression. This committee evaluated multiple drugs currently used, or being developed, in other therapeutic areas, as well as considering several natural, non-pharmaceutical compounds. The committee prioritized which of these putative treatments were most suited to move immediately into pilot clinical trials. Aspects considered included known modes of action, safety, blood-brain-barrier penetration, preclinical data in animal models of PD and the possibility to monitor target engagement in the brain. Of the 26 potential interventions, 10 were considered worth moving forward into small, parallel 'learning' clinical trials in PD patients. These trials could be funded in a multitude of ways through support from industry, research grants and directed philanthropic donations. The committee-based approach to select the candidate compounds might help rapidly identify new potential PD treatment strategies for use in clinical trials.

10 Review New synaptic and molecular targets for neuroprotection in Parkinson's disease. 2013

Calabresi, Paolo / Di Filippo, Massimiliano / Gallina, Antongiulio / Wang, Yingfei / Stankowski, Jeannette N / Picconi, Barbara / Dawson, Valina L / Dawson, Ted M. ·Clinical Neurology, University of Perugia, Perugia, Italy. calabre@unipg.it ·Mov Disord · Pubmed #22927178.

ABSTRACT: The defining anatomical feature of Parkinson's disease (PD) is the degeneration of substantia nigra pars compacta (SNc) neurons, resulting in striatal dopamine (DA) deficiency and in the subsequent alteration of basal ganglia physiology. Treatments targeting the dopaminergic system alleviate PD symptoms but are not able to slow the neurodegenerative process that underlies PD progression. The nucleus striatum comprises a complex network of projecting neurons and interneurons that integrates different neural signals to modulate the activity of the basal ganglia circuitry. In this review we describe new potential molecular and synaptic striatal targets for the development of both symptomatic and neuroprotective strategies for PD. In particular, we focus on the interaction between adenosine A2A receptors and dopamine D2 receptors, on the role of a correct assembly of NMDA receptors, and on the sGC/cGMP/PKG pathway. Moreover, we also discuss the possibility to target the cell death program parthanatos and the kinase LRRK2 in order to develop new putative neuroprotective agents for PD acting on dopaminergic nigral neurons as well as on other basal ganglia structures.

11 Review LRRK2 GTPase dysfunction in the pathogenesis of Parkinson's disease. 2012

Xiong, Yulan / Dawson, Valina L / Dawson, Ted M. ·Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. ·Biochem Soc Trans · Pubmed #22988868.

ABSTRACT: Mutations in the LRRK2 (leucine-rich repeat kinase 2) gene are the most frequent genetic cause of PD (Parkinson's disease), and these mutations play important roles in sporadic PD. The LRRK2 protein contains GTPase and kinase domains and several protein-protein interaction domains. The kinase and GTPase activity of LRRK2 seem to be important in regulating LRRK2-dependent cellular signalling pathways. LRRK2's GTPase and kinase domains may reciprocally regulate each other to direct LRRK2's ultimate function. Although most LRRK2 investigations are centred on LRRK2's kinase activity, the present review focuses on the function of LRRK2's GTPase activity in LRRK2 physiology and pathophysiology.

12 Review Animal models of Parkinson's disease: vertebrate genetics. 2012

Lee, Yunjong / Dawson, Valina L / Dawson, Ted M. ·NeuroRegeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA. ·Cold Spring Harb Perspect Med · Pubmed #22960626.

ABSTRACT: Parkinson's disease (PD) is a complex genetic disorder that is associated with environmental risk factors and aging. Vertebrate genetic models, especially mice, have aided the study of autosomal-dominant and autosomal-recessive PD. Mice are capable of showing a broad range of phenotypes and, coupled with their conserved genetic and anatomical structures, provide unparalleled molecular and pathological tools to model human disease. These models used in combination with aging and PD-associated toxins have expanded our understanding of PD pathogenesis. Attempts to refine PD animal models using conditional approaches have yielded in vivo nigrostriatal degeneration that is instructive in ordering pathogenic signaling and in developing therapeutic strategies to cure or halt the disease. Here, we provide an overview of the generation and characterization of transgenic and knockout mice used to study PD followed by a review of the molecular insights that have been gleaned from current PD mouse models. Finally, potential approaches to refine and improve current models are discussed.

13 Review Leucine-rich repeat kinase 2 (LRRK2) as a potential therapeutic target in Parkinson's disease. 2012

Lee, Byoung Dae / Dawson, Valina L / Dawson, Ted M. ·Age-Related and Brain Disease Research Center, Kyung Hee University, Seoul, South Korea. ·Trends Pharmacol Sci · Pubmed #22578536.

ABSTRACT: Parkinson's disease (PD) is caused by the progressive degeneration of dopaminergic neurons in the substantia nigra. Although the etiology for most PD remains elusive, the identification of specific genetic defects in familial cases of PD and the signaling pathways governed by these genes has provided tremendous insight into PD pathogenesis. Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are frequently found in familial and sporadic PD. Although current knowledge regarding the regulatory mechanisms of LRRK2 activation is limited, it is becoming increasingly evident that aberrant kinase activity of the pathologic mutants of LRRK2 is associated with neurodegeneration, suggesting that the kinase activity of LRRK2 is a potential therapeutic target. In addition, LRRK2 inhibitors might provide valuable tools to understand the pathophysiological and physiological roles of LRRK2 as well as the etiology of PD. We discuss here the potential and feasibility of targeting LRRK2 as a therapeutic strategy for PD.

14 Review Recent advances in the genetics of Parkinson's disease. 2011

Martin, Ian / Dawson, Valina L / Dawson, Ted M. ·NeuroRegeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA. imarti11@jhmi.edu ·Annu Rev Genomics Hum Genet · Pubmed #21639795.

ABSTRACT: Genetic studies have provided valuable insight into the pathological mechanisms underlying Parkinson's disease (PD). The elucidation of genetic components to what was once largely considered a nongenetic disease has given rise to a multitude of cell and animal models enabling the dissection of molecular pathways involved in disease etiology. Here, we review advances obtained from models of dominant mutations in α-synuclein and LRRK2 as well as recessive PINK1, parkin and DJ-1 mutations. Recent genome-wide association studies have implicated genetic variability at two of these loci, α-synuclein and LRRK2, as significant risk factors for developing sporadic PD. This, coupled with the established role of mitochondrial impairment in both familial and sporadic PD, highlights the likelihood of common mechanisms fundamental to the etiology of both.

15 Review MicroRNAs in Parkinson's disease. 2011

Harraz, Maged M / Dawson, Ted M / Dawson, Valina L. ·Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. ·J Chem Neuroanat · Pubmed #21295133.

ABSTRACT: MicroRNAs are small non-protein coding RNAs that regulate gene expression through post-transcriptional repression. Recent studies demonstrated the importance of microRNAs in the nervous system development, function and disease. Parkinson's disease is the second most prevalent neurodegenerative disease with only symptomatic treatment available. Recent success in using small RNAs as therapeutic targets hold a substantial promise for the Parkinson's disease field. Here we review recent work linking the microRNA pathway to Parkinson's disease.

16 Review Genetic animal models of Parkinson's disease. 2010

Dawson, Ted M / Ko, Han Seok / Dawson, Valina L. ·Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. tdawson@jhmi.edu ·Neuron · Pubmed #20547124.

ABSTRACT: Parkinson's disease (PD) is a progressive neurodegenerative disorder that is characterized by the degeneration of dopamine (DA) and non-DA neurons, the almost uniform presence of Lewy bodies, and motor deficits. Although the majority of PD is sporadic, specific genetic defects in rare familial cases have provided unique insights into the pathogenesis of PD. Through the creation of animal and cellular models of mutations in LRRK2 and alpha-synuclein, which are linked to autosomal-dominant PD, and mutations in parkin, DJ-1, and PINK1, which are responsible for autosomal-recessive PD, insight into the molecular mechanisms of this disorder are leading to new ideas about the pathogenesis of PD. In this review, we discuss the animal models for these genetic causes of PD, their limitations, and value. Moreover, we discuss future directions and potential strategies for optimization of the genetic models.

17 Review The role of parkin in familial and sporadic Parkinson's disease. 2010

Dawson, Ted M / Dawson, Valina L. ·Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA. tdawson@jhmi.edu ·Mov Disord · Pubmed #20187240.

ABSTRACT: Mutations in parkin are the second most common known cause of Parkinson's disease (PD). Parkin is an ubiquitin E3 ligase that monoubiquitinates and polyubiquitinates proteins to regulate a variety of cellular processes. Loss of parkin's E3 ligase activity is thought to play a pathogenic role in both inherited and sporadic PD. Here, we review parkin biology and pathobiology and its role in the pathogenesis of PD.

18 Clinical Trial A randomized clinical trial of high-dosage coenzyme Q10 in early Parkinson disease: no evidence of benefit. 2014

Anonymous1120789 / Beal, M Flint / Oakes, David / Shoulson, Ira / Henchcliffe, Claire / Galpern, Wendy R / Haas, Richard / Juncos, Jorge L / Nutt, John G / Voss, Tiffini Smith / Ravina, Bernard / Shults, Clifford M / Helles, Karen / Snively, Victoria / Lew, Mark F / Griebner, Brian / Watts, Arthur / Gao, Shan / Pourcher, Emmanuelle / Bond, Louisette / Kompoliti, Katie / Agarwal, Pinky / Sia, Cherissa / Jog, Mandar / Cole, Linda / Sultana, Munira / Kurlan, Roger / Richard, Irene / Deeley, Cheryl / Waters, Cheryl H / Figueroa, Angel / Arkun, Ani / Brodsky, Matthew / Ondo, William G / Hunter, Christine B / Jimenez-Shahed, Joohi / Palao, Alicia / Miyasaki, Janis M / So, Julie / Tetrud, James / Reys, Liza / Smith, Katharine / Singer, Carlos / Blenke, Anita / Russell, David S / Cotto, Candace / Friedman, Joseph H / Lannon, Margaret / Zhang, Lin / Drasby, Edward / Kumar, Rajeev / Subramanian, Thyagarajan / Ford, Donna Stuppy / Grimes, David A / Cote, Diane / Conway, Jennifer / Siderowf, Andrew D / Evatt, Marian Leslie / Sommerfeld, Barbara / Lieberman, Abraham N / Okun, Michael S / Rodriguez, Ramon L / Merritt, Stacy / Swartz, Camille Louise / Martin, W R Wayne / King, Pamela / Stover, Natividad / Guthrie, Stephanie / Watts, Ray L / Ahmed, Anwar / Fernandez, Hubert H / Winters, Adrienna / Mari, Zoltan / Dawson, Ted M / Dunlop, Becky / Feigin, Andrew S / Shannon, Barbara / Nirenberg, Melissa Jill / Ogg, Mattson / Ellias, Samuel A / Thomas, Cathi-Ann / Frei, Karen / Bodis-Wollner, Ivan / Glazman, Sofya / Mayer, Thomas / Hauser, Robert A / Pahwa, Rajesh / Langhammer, April / Ranawaya, Ranjit / Derwent, Lorelei / Sethi, Kapil D / Farrow, Buff / Prakash, Rajan / Litvan, Irene / Robinson, Annette / Sahay, Alok / Gartner, Maureen / Hinson, Vanessa K / Markind, Samuel / Pelikan, Melisa / Perlmutter, Joel S / Hartlein, Johanna / Molho, Eric / Evans, Sharon / Adler, Charles H / Duffy, Amy / Lind, Marlene / Elmer, Lawrence / Davis, Kathy / Spears, Julia / Wilson, Stephanie / Leehey, Maureen A / Hermanowicz, Neal / Niswonger, Shari / Shill, Holly A / Obradov, Sanja / Rajput, Alex / Cowper, Marilyn / Lessig, Stephanie / Song, David / Fontaine, Deborah / Zadikoff, Cindy / Williams, Karen / Blindauer, Karen A / Bergholte, Jo / Propsom, Clara Schindler / Stacy, Mark A / Field, Joanne / Mihaila, Dragos / Chilton, Mark / Uc, Ergun Y / Sieren, Jeri / Simon, David K / Kraics, Lauren / Silver, Althea / Boyd, James T / Hamill, Robert W / Ingvoldstad, Christopher / Young, Jennifer / Thomas, Karen / Kostyk, Sandra K / Wojcieszek, Joanne / Pfeiffer, Ronald F / Panisset, Michel / Beland, Monica / Reich, Stephen G / Cines, Michelle / Zappala, Nancy / Rivest, Jean / Zweig, Richard / Lumina, L Pepper / Hilliard, Colette Lynn / Grill, Stephen / Kellermann, Marye / Tuite, Paul / Rolandelli, Susan / Kang, Un Jung / Young, Joan / Rao, Jayaraman / Cook, Maureen M / Severt, Lawrence / Boyar, Karyn. ·Department of Neurology, Weill Cornell Medical College, New York Hospital, New York. · Department of Biostatistics, University of Rochester Medical Center, Rochester, New York. · Department of Neurology, Georgetown University, Washington, DC. · National Institutes of Health, Bethesda, Maryland. · Department of Neurosciences, University of California, San Diego, La Jolla. · Department of Neurology, Emory University School of Medicine, Wesley Woods Center, Atlanta, Georgia. · Department of Neurology, Oregon Health and Science University, Portland. · Merck, New Jersey. · Biogen Idec, Cambridge, Massachusetts. · Department of Neurosciences, University of California, San Diego, La Jolla10VA Medical Center, San Diego, California. · Department of Neurology, Keck School of Medicine, University of Southern California, Los Angeles. · Department of Biostatistics, University of Rochester Medical Center, Rochester, New York12Department of Neurology, University of Rochester, Rochester, New York. · Québec Memory and Motor Skills Disorders Research Center, Clinique Sainte-Anne, Québec, Canada. · Rush University Medical Center, Chicago, Illinois. · Booth Gardner Parkinson's Care Center, EvergreenHealth, Kirkland, Washington. · London Health Sciences Centre, London, Ontario, Canada. · Overlook Medical Center, Atlantic Neuroscience Institute, Summit, New Jersey. · Department of Neurology, University of Rochester, Rochester, New York. · Columbia University Medical Center, Neurological Institute, New York, New York. · Department of Neurology, University of Texas Health Science Center at Houston. · Department of Neurology, Baylor College of Medicine, Houston, Texas. · Morton and Gloria Shulman Movement Disorders Centre, Toronto Western Hospital, University of Toronto, Toronto, Ontario, Canada. · The Parkinson's Institute and Clinical Center, Sunnyvale, California. · Department of Neurology, University of Miami School of Medicine, Miami, Florida. · Institute for Neurodegenerative Disorders, New Haven, Connecticut. · Department of Neurology, Butler Hospital, Providence, Rhode Island26Alpert Medical School, Brown University, Providence, Rhode Island. · Department of Neurology, Butler Hospital, Providence, Rhode Island27Port City Neurology, Inc, Scarborough, Maine. · Department of Neurology, University of California, Davis, School of Medicine and Sacramento VA Medical Center, Sacramento. · Port City Neurology, Inc, Scarborough, Maine. · Colorado Neurological Institute, Englewood. · Milton S. Hershey Medical Center, Department of Neurology, Pennsylvania State Hershey College of Medicine, Hershey. · Ottawa Hospital Civic Site, Ottawa, Ontario, Canada. · Avid Radiopharmaceuticals, Philadelphia, Pennsylvania. · Department of Neurology, Emory University School of Medicine, Wesley Woods Center, Atlanta, Georgia33Atlanta VA Medical Center, Atlanta, Georgia. · Muhammad Ali Parkinson Center, Barrow Neurological Institute, St Joseph's Hospital and Medical Center, Phoenix, Arizona. · Department of Neurology, University of Florida Center for Movement Disorders and Neurorestoration, Gainesville. · Glenrose Rehabilitation Hospital, University of Alberta, Edmonton, Alberta, Canada. · Department of Neurology, University of Alabama at Birmingham. · Center for Neurological Restoration, Department of Neurology, Cleveland Clinic, Cleveland, Ohio. · Department of Neurology, Johns Hopkins University, Baltimore, Maryland. · Feinstein Institute for Medical Research, Center for Neurosciences, Manhasset, New York. · Department of Neurology, New York University Langone Medical Center, New York. · Department of Neurology, Boston University School of Medicine, Boston, Massachusetts. · The Parkinson's and Movement Disorder Institute, Fountain Valley, California. · State University of New York, Downstate Medical Center, Brooklyn, New York. · Department of Neurology, University of South Florida, Tampa. · Department of Neurology, University of Kansas Medical Center, Kansas City. · Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta, Canada. · Department of Neurology, Georgia Health Science University, Augusta. · Department of Neurology, University of Louisville, Kentucky. · University of Cincinnati College of Medicine, Cincinnati, Ohio. · Department of Neurology, Medical University of South Carolina, Charleston. · Associated Neurologists, PC, Danbury, Connecticut. · Department of Neurology, Washington University in St Louis, Missouri. · Movement Disorders Center, Albany Medical Center, Albany, New York. · Parkinson's Disease and Movement Disorders Center, Department of Neurology, Mayo Clinic, Scottsdale, Arizona. · Center for Neurological Health, University of Toledo, Toledo, Ohio. · Department of Neurology, Medical University of Ohio at Toledo. · Department of Neurology, University of Colorado Health Science Center, Denver. · Department of Neurology, University of California, Irvine Medical Center, Irvine. · Banner Sun Health Research Institute, Sun City, Arizona. · Department of Neurology, University of Saskatchewan, Royal University Hospital, Saskatchewan, Canada. · Department of Neurology, University of California, San Diego, La Jolla. · Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, Illinois. · Department of Neurology, Medical College of Wisconsin, Milwaukee. · Department of Neurology, Duke University, Durham, North Carolina. · State University of New York Upstate Medical Center and Syracuse VA Medical Center, Syracuse. · Department of Neurology, University of Iowa, Iowa City. · Department of Neurology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts. · Department of Neurology, University of Vermont College of Medicine, Burlington. · Department of Neurology, Ohio State University, Columbus. · Department of Neurology, Indiana University School of Medicine, Indianapolis. · Department of Neurology, University of Tennessee Health Science Center, Memphis. · Department of Neurology, CHUM-Hôpital Notre-Dame, Montréal, Québec, Canada. · Department of Neurology, University of Maryland School of Science, Baltimore. · Department of Neurology, University of Sherbrooke, Québec, Canada. · Department of Neurology, Louisiana State University Health Science Center, Shreveport. · Lewis Hall Singletary Oncology Center, Thomasville, Georgia. · Parkinson and Movement Disorders Center of Maryland, Elkridge. · Department of Neurology, University of Minnesota, Minneapolis. · Department of Neurology, University of Chicago, Chicago, Illinois. · Department of Neurology, Ochsner Clinic Foundation, New Orleans, Louisiana. · Department of Neurology, Beth Israel Medical Center, New York, New York. ·JAMA Neurol · Pubmed #24664227.

ABSTRACT: IMPORTANCE: Coenzyme Q10 (CoQ10), an antioxidant that supports mitochondrial function, has been shown in preclinical Parkinson disease (PD) models to reduce the loss of dopamine neurons, and was safe and well tolerated in early-phase human studies. A previous phase II study suggested possible clinical benefit. OBJECTIVE: To examine whether CoQ10 could slow disease progression in early PD. DESIGN, SETTING, AND PARTICIPANTS: A phase III randomized, placebo-controlled, double-blind clinical trial at 67 North American sites consisting of participants 30 years of age or older who received a diagnosis of PD within 5 years and who had the following inclusion criteria: the presence of a rest tremor, bradykinesia, and rigidity; a modified Hoehn and Yahr stage of 2.5 or less; and no anticipated need for dopaminergic therapy within 3 months. Exclusion criteria included the use of any PD medication within 60 days, the use of any symptomatic PD medication for more than 90 days, atypical or drug-induced parkinsonism, a Unified Parkinson's Disease Rating Scale (UPDRS) rest tremor score of 3 or greater for any limb, a Mini-Mental State Examination score of 25 or less, a history of stroke, the use of certain supplements, and substantial recent exposure to CoQ10. Of 696 participants screened, 78 were found to be ineligible, and 18 declined participation. INTERVENTIONS: The remaining 600 participants were randomly assigned to receive placebo, 1200 mg/d of CoQ10, or 2400 mg/d of CoQ10; all participants received 1200 IU/d of vitamin E. MAIN OUTCOMES AND MEASURES: Participants were observed for 16 months or until a disability requiring dopaminergic treatment. The prospectively defined primary outcome measure was the change in total UPDRS score (Parts I-III) from baseline to final visit. The study was powered to detect a 3-point difference between an active treatment and placebo. RESULTS: The baseline characteristics of the participants were well balanced, the mean age was 62.5 years, 66% of participants were male, and the mean baseline total UPDRS score was 22.7. A total of 267 participants required treatment (94 received placebo, 87 received 1200 mg/d of CoQ10, and 86 received 2400 mg/d of CoQ10), and 65 participants (29 who received placebo, 19 who received 1200 mg/d of CoQ10, and 17 who received 2400 mg/d of CoQ10) withdrew prematurely. Treatments were well tolerated with no safety concerns. The study was terminated after a prespecified futility criterion was reached. At study termination, both active treatment groups showed slight adverse trends relative to placebo. Adjusted mean changes (worsening) in total UPDRS scores from baseline to final visit were 6.9 points (placebo), 7.5 points (1200 mg/d of CoQ10; P = .49 relative to placebo), and 8.0 points (2400 mg/d of CoQ10; P = .21 relative to placebo). CONCLUSIONS AND RELEVANCE: Coenzyme Q10 was safe and well tolerated in this population, but showed no evidence of clinical benefit. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00740714.

19 Article PARIS induced defects in mitochondrial biogenesis drive dopamine neuron loss under conditions of parkin or PINK1 deficiency. 2020

Pirooznia, Sheila K / Yuan, Changqing / Khan, Mohammed Repon / Karuppagounder, Senthilkumar S / Wang, Luan / Xiong, Yulan / Kang, Sung Ung / Lee, Yunjong / Dawson, Valina L / Dawson, Ted M. ·Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, 733 North Broadway, Suite 731, Baltimore, MD, 21205, USA. · Departments of Neurology, Iowa City, USA. · Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA, 70130-2685, USA. · Diana Helis Henry Medical Research Foundation, New Orleans, LA, 70130-2685, USA. · Department of Anatomy and Physiology, College of Veterinary Medicine, Kansas State University, Manhattan, KS, 66506, USA. · Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, 733 North Broadway, Suite 731, Baltimore, MD, 21205, USA. vdawson@jhmi.edu. · Departments of Neurology, Iowa City, USA. vdawson@jhmi.edu. · Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA, 70130-2685, USA. vdawson@jhmi.edu. · Diana Helis Henry Medical Research Foundation, New Orleans, LA, 70130-2685, USA. vdawson@jhmi.edu. · Departments of Physiology, Baltimore, USA. vdawson@jhmi.edu. · Solomon H. Snyder Department of Neuroscience, Baltimore, USA. vdawson@jhmi.edu. · Solomon H. Snyder Department of Neuroscience, Baltimore, USA. · Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. ·Mol Neurodegener · Pubmed #32138754.

ABSTRACT: BACKGROUND: Mutations in PINK1 and parkin cause autosomal recessive Parkinson's disease (PD). Evidence placing PINK1 and parkin in common pathways regulating multiple aspects of mitochondrial quality control is burgeoning. However, compelling evidence to causatively link specific PINK1/parkin dependent mitochondrial pathways to dopamine neuron degeneration in PD is lacking. Although PINK1 and parkin are known to regulate mitophagy, emerging data suggest that defects in mitophagy are unlikely to be of pathological relevance. Mitochondrial functions of PINK1 and parkin are also tied to their proteasomal regulation of specific substrates. In this study, we examined how PINK1/parkin mediated regulation of the pathogenic substrate PARIS impacts dopaminergic mitochondrial network homeostasis and neuronal survival in Drosophila. METHODS: The UAS-Gal4 system was employed for cell-type specific expression of the various transgenes. Effects on dopamine neuronal survival and function were assessed by anti-TH immunostaining and negative geotaxis assays. Mitochondrial effects were probed by quantitative analysis of mito-GFP labeled dopaminergic mitochondria, assessment of mitochondrial abundance in dopamine neurons isolated by Fluorescence Activated Cell Sorting (FACS) and qRT-PCR analysis of dopaminergic factors that promote mitochondrial biogenesis. Statistical analyses employed two-tailed Student's T-test, one-way or two-way ANOVA as required and data considered significant when P < 0.05. RESULTS: We show that defects in mitochondrial biogenesis drive adult onset progressive loss of dopamine neurons and motor deficits in Drosophila models of PINK1 or parkin insufficiency. Such defects result from PARIS dependent repression of dopaminergic PGC-1α and its downstream transcription factors NRF1 and TFAM that cooperatively promote mitochondrial biogenesis. Dopaminergic accumulation of human or Drosophila PARIS recapitulates these neurodegenerative phenotypes that are effectively reversed by PINK1, parkin or PGC-1α overexpression in vivo. To our knowledge, PARIS is the only co-substrate of PINK1 and parkin to specifically accumulate in the DA neurons and cause neurodegeneration and locomotor defects stemming from disrupted dopamine signaling. CONCLUSIONS: Our findings identify a highly conserved role for PINK1 and parkin in regulating mitochondrial biogenesis and promoting mitochondrial health via the PARIS/ PGC-1α axis. The Drosophila models described here effectively recapitulate the cardinal PD phenotypes and thus will facilitate identification of novel regulators of mitochondrial biogenesis for physiologically relevant therapeutic interventions.

20 Article Genetic modifiers of risk and age at onset in GBA associated Parkinson's disease and Lewy body dementia. 2020

Blauwendraat, Cornelis / Reed, Xylena / Krohn, Lynne / Heilbron, Karl / Bandres-Ciga, Sara / Tan, Manuela / Gibbs, J Raphael / Hernandez, Dena G / Kumaran, Ravindran / Langston, Rebekah / Bonet-Ponce, Luis / Alcalay, Roy N / Hassin-Baer, Sharon / Greenbaum, Lior / Iwaki, Hirotaka / Leonard, Hampton L / Grenn, Francis P / Ruskey, Jennifer A / Sabir, Marya / Ahmed, Sarah / Makarious, Mary B / Pihlstrøm, Lasse / Toft, Mathias / van Hilten, Jacobus J / Marinus, Johan / Schulte, Claudia / Brockmann, Kathrin / Sharma, Manu / Siitonen, Ari / Majamaa, Kari / Eerola-Rautio, Johanna / Tienari, Pentti J / Anonymous21571124 / Pantelyat, Alexander / Hillis, Argye E / Dawson, Ted M / Rosenthal, Liana S / Albert, Marilyn S / Resnick, Susan M / Ferrucci, Luigi / Morris, Christopher M / Pletnikova, Olga / Troncoso, Juan / Grosset, Donald / Lesage, Suzanne / Corvol, Jean-Christophe / Brice, Alexis / Noyce, Alastair J / Masliah, Eliezer / Wood, Nick / Hardy, John / Shulman, Lisa M / Jankovic, Joseph / Shulman, Joshua M / Heutink, Peter / Gasser, Thomas / Cannon, Paul / Scholz, Sonja W / Morris, Huw / Cookson, Mark R / Nalls, Mike A / Gan-Or, Ziv / Singleton, Andrew B. ·Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA. · Department of Human Genetics, McGill University, Montreal, Quebec, Canada. · Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada. · 23andMe, Inc., Mountain View, CA, USA. · Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK. · Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, NY, USA. · Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, NY, USA. · Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. · Department of Neurology, Sheba Medical Center, Tel Hashomer, Israel. · Movement Disorders Institute, Sheba Medical Center, Tel Hashomer, Israel. · The Joseph Sagol Neuroscience Center, Sheba Medical Center, Tel Hashomer, Israel. · The Danek Gertner Institute of Human Genetics, Sheba Medical Center, Tel Hashomer, Israel. · Neurodegenerative Diseases Research Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA. · Department of Neurology, Oslo University Hospital, Oslo, Norway. · Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands. · Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany. · German Center for Neurodegenerative Diseases (DZNE), Tuebingen, Germany. · Centre for Genetic Epidemiology, Institute for Clinical Epidemiology and Applied Biometry, University of Tubingen, Germany. · Institute of Clinical Medicine, Department of Neurology, University of Oulu, Oulu, Finland. · Department of Neurology and Medical Research Center, Oulu University Hospital, Oulu, Finland. · Department of Neurology, Helsinki University Hospital, and Molecular Neurology, Research Programs Unit, Biomedicum, University of Helsinki, Helsinki, Finland. · Neuroregeneration and Stem Cell Program, Institute for Cell Engineering, Johns Hopkins University Medical Center, Baltimore, MD, USA. · Department of Neurology, Johns Hopkins University Medical Center, Baltimore, MD, USA. · Laboratory of Behavioral Neuroscience, National Institute on Aging, Baltimore, MD, USA. · Longitudinal Studies Section, National Institute on Aging, Baltimore, MD, USA. · Newcastle Brain Tissue Resource, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, UK. · Department of Pathology (Neuropathology, Johns Hopkins University Medical Center, Baltimore, MD, USA. · Department of Neurology, Institute of Neurological Sciences, Queen Elizabeth University Hospital, Glasgow, UK. · Inserm U1127, Sorbonne Universités, UPMC Univ Paris 06 UMR S1127, Institut du Cerveau et de la Moelle épinière, ICM, Paris, France. · Preventive Neurology Unit, Wolfson Institute of Preventive Medicine, Queen Mary University of London, London, UK. · Department of Neurodegenerative Diseases, UCL Queen Square Institute of Neurology, London, UK. · Department of Neurology, University of Maryland School of Medicine, Baltimore, MD, USA. · Department of Neurology, Baylor College of Medicine, Houston, USA. · Departments of Molecular and Human Genetics and Neuroscience, Baylor College of Medicine, Houston, USA. · Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, USA. · Data Tecnica International, Glen Echo, MD, USA. · Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada. ·Brain · Pubmed #31755958.

ABSTRACT: Parkinson's disease is a genetically complex disorder. Multiple genes have been shown to contribute to the risk of Parkinson's disease, and currently 90 independent risk variants have been identified by genome-wide association studies. Thus far, a number of genes (including SNCA, LRRK2, and GBA) have been shown to contain variability across a spectrum of frequency and effect, from rare, highly penetrant variants to common risk alleles with small effect sizes. Variants in GBA, encoding the enzyme glucocerebrosidase, are associated with Lewy body diseases such as Parkinson's disease and Lewy body dementia. These variants, which reduce or abolish enzymatic activity, confer a spectrum of disease risk, from 1.4- to >10-fold. An outstanding question in the field is what other genetic factors that influence GBA-associated risk for disease, and whether these overlap with known Parkinson's disease risk variants. Using multiple, large case-control datasets, totalling 217 165 individuals (22 757 Parkinson's disease cases, 13 431 Parkinson's disease proxy cases, 622 Lewy body dementia cases and 180 355 controls), we identified 1691 Parkinson's disease cases, 81 Lewy body dementia cases, 711 proxy cases and 7624 controls with a GBA variant (p.E326K, p.T369M or p.N370S). We performed a genome-wide association study and analysed the most recent Parkinson's disease-associated genetic risk score to detect genetic influences on GBA risk and age at onset. We attempted to replicate our findings in two independent datasets, including the personal genetics company 23andMe, Inc. and whole-genome sequencing data. Our analysis showed that the overall Parkinson's disease genetic risk score modifies risk for disease and decreases age at onset in carriers of GBA variants. Notably, this effect was consistent across all tested GBA risk variants. Dissecting this signal demonstrated that variants in close proximity to SNCA and CTSB (encoding cathepsin B) are the most significant contributors. Risk variants in the CTSB locus were identified to decrease mRNA expression of CTSB. Additional analyses suggest a possible genetic interaction between GBA and CTSB and GBA p.N370S induced pluripotent cell-derived neurons were shown to have decreased cathepsin B expression compared to controls. These data provide a genetic basis for modification of GBA-associated Parkinson's disease risk and age at onset, although the total contribution of common genetics variants is not large. We further demonstrate that common variability at genes implicated in lysosomal function exerts the largest effect on GBA associated risk for disease. Further, these results have implications for selection of GBA carriers for therapeutic interventions.

21 Article Transneuronal Propagation of Pathologic α-Synuclein from the Gut to the Brain Models Parkinson's Disease. 2019

Kim, Sangjune / Kwon, Seung-Hwan / Kam, Tae-In / Panicker, Nikhil / Karuppagounder, Senthilkumar S / Lee, Saebom / Lee, Jun Hee / Kim, Wonjoong Richard / Kook, Minjee / Foss, Catherine A / Shen, Chentian / Lee, Hojae / Kulkarni, Subhash / Pasricha, Pankaj J / Lee, Gabsang / Pomper, Martin G / Dawson, Valina L / Dawson, Ted M / Ko, Han Seok. ·Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. · The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. · Center for Neurogastroenterology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. · Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. · Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. · Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Electronic address: tdawson@jhmi.edu. · Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130, USA. Electronic address: hko3@jhmi.edu. ·Neuron · Pubmed #31255487.

ABSTRACT: Analysis of human pathology led Braak to postulate that α-synuclein (α-syn) pathology could spread from the gut to brain via the vagus nerve. Here, we test this postulate by assessing α-synucleinopathy in the brain in a novel gut-to-brain α-syn transmission mouse model, where pathological α-syn preformed fibrils were injected into the duodenal and pyloric muscularis layer. Spread of pathologic α-syn in brain, as assessed by phosphorylation of serine 129 of α-syn, was observed first in the dorsal motor nucleus, then in caudal portions of the hindbrain, including the locus coeruleus, and much later in basolateral amygdala, dorsal raphe nucleus, and the substantia nigra pars compacta. Moreover, loss of dopaminergic neurons and motor and non-motor symptoms were observed in a similar temporal manner. Truncal vagotomy and α-syn deficiency prevented the gut-to-brain spread of α-synucleinopathy and associated neurodegeneration and behavioral deficits. This study supports the Braak hypothesis in the etiology of idiopathic Parkinson's disease (PD).

22 Article Parkin interacting substrate zinc finger protein 746 is a pathological mediator in Parkinson's disease. 2019

Brahmachari, Saurav / Lee, Saebom / Kim, Sangjune / Yuan, Changqing / Karuppagounder, Senthilkumar S / Ge, Preston / Shi, Rosa / Kim, Esther J / Liu, Alex / Kim, Donghoon / Quintin, Stephan / Jiang, Haisong / Kumar, Manoj / Yun, Seung Pil / Kam, Tae-In / Mao, Xiaobo / Lee, Yunjong / Swing, Deborah A / Tessarollo, Lino / Ko, Han Seok / Dawson, Valina L / Dawson, Ted M. ·Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. · Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. · Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130-2685, USA. · Diana Helis Henry Medical Research Foundation, New Orleans, LA 70130-2685, USA. · Neural Development Section, Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute, Frederick, Maryland, USA. · Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. · Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. · Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. ·Brain · Pubmed #31237944.

ABSTRACT: α-Synuclein misfolding and aggregation plays a major role in the pathogenesis of Parkinson's disease. Although loss of function mutations in the ubiquitin ligase, parkin, cause autosomal recessive Parkinson's disease, there is evidence that parkin is inactivated in sporadic Parkinson's disease. Whether parkin inactivation is a driver of neurodegeneration in sporadic Parkinson's disease or a mere spectator is unknown. Here we show that parkin in inactivated through c-Abelson kinase phosphorylation of parkin in three α-synuclein-induced models of neurodegeneration. This results in the accumulation of parkin interacting substrate protein (zinc finger protein 746) and aminoacyl tRNA synthetase complex interacting multifunctional protein 2 with increased parkin interacting substrate protein levels playing a critical role in α-synuclein-induced neurodegeneration, since knockout of parkin interacting substrate protein attenuates the degenerative process. Thus, accumulation of parkin interacting substrate protein links parkin inactivation and α-synuclein in a common pathogenic neurodegenerative pathway relevant to both sporadic and familial forms Parkinson's disease. Thus, suppression of parkin interacting substrate protein could be a potential therapeutic strategy to halt the progression of Parkinson's disease and related α-synucleinopathies.

23 Article The A1 astrocyte paradigm: New avenues for pharmacological intervention in neurodegeneration. 2019

Hinkle, Jared T / Dawson, Valina L / Dawson, Ted M. ·Medical Scientist Training Program, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. · Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. · Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. · Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. · Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. · Adrienne Helis Malvin Medical Research Foundation, New Orleans, Louisiana, USA. · Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. ·Mov Disord · Pubmed #31136698.

ABSTRACT: We recently demonstrated that NLY01, a novel glucagon-like peptide-1 receptor agonist, exerts neuroprotective effects in two mouse models of PD in a glia-dependent manner. NLY01 prevented microglia from releasing inflammatory mediators known to convert astrocytes into a neurotoxic A1 reactive subtype. Importantly, we provided evidence that this neuroprotection was not mediated by a direct action of NLY01 on neurons or astrocytes (e.g., by activating neurotrophic pathways or modulating astrocyte reactivity per se). In the present article, we provide a generalist review of microglia and astrocytes in neurodegeneration and discuss the emerging paradigm of A1 astrocyte neurotoxicity in more detail. We comment on specific inferences that are naturally suggested by our work in this area and the differential level of support it offers to each. Finally, we discuss implications for the overall goal of creating disease-modifying therapies for PD, survey emerging methodologies for accelerating translational research on glia in neurodegeneration, and describe expected challenges for developing glia-directed therapies that do not impede essential physiological functions carried out by glia in the CNS. © 2019 International Parkinson and Movement Disorder Society.

24 Article Assessment of APOE in atypical parkinsonism syndromes. 2019

Sabir, Marya S / Blauwendraat, Cornelis / Ahmed, Sarah / Serrano, Geidy E / Beach, Thomas G / Perkins, Matthew / Rice, Ann C / Masliah, Eliezer / Morris, Christopher M / Pihlstrom, Lasse / Pantelyat, Alexander / Resnick, Susan M / Cookson, Mark R / Hernandez, Dena G / Albert, Marilyn / Dawson, Ted M / Rosenthal, Liana S / Houlden, Henry / Pletnikova, Olga / Troncoso, Juan / Scholz, Sonja W. ·Neurodegenerative Diseases Research Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA. · Civin Laboratory of Neuropathology, Banner Sun Health Research Institute, Sun City, AZ, USA. · Michigan Brain Bank, University of Michigan Medical School, Ann Arbor, MI, USA. · Virginia Commonwealth University Brain Bank, Virginia Commonwealth University, Richmond, VA, USA. · Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA. · Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, UK. · Department of Neurology, Oslo University Hospital, Oslo, Norway. · Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. · Laboratory of Behavioral Neuroscience, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA. · Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Neuroregeneration and Stem Cell Programs, Institute of Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA. · Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK. · Department of Pathology (Neuropathology), Johns Hopkins University Medical Center, Baltimore, MD, USA. · Neurodegenerative Diseases Research Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Electronic address: sonja.scholz@nih.gov. ·Neurobiol Dis · Pubmed #30798004.

ABSTRACT: Atypical parkinsonism syndromes are a heterogeneous group of neurodegenerative disorders that include corticobasal degeneration (CBD), Lewy body dementia (LBD), multiple system atrophy (MSA), and progressive supranuclear palsy (PSP). The APOE ε4 allele is a well-established risk factor for Alzheimer's disease; however, the role of APOE in atypical parkinsonism syndromes remains controversial. To examine the associations of APOE ε4 and ε2 alleles with risk of developing these syndromes, a total of 991 pathologically-confirmed atypical parkinsonism cases were genotyped using the Illumina NeuroChip array. We also performed genotyping and logistic regression analyses to examine APOE frequency and associated risk in patients with Alzheimer's disease (n = 571) and Parkinson's disease (n = 348). APOE genotypes were compared to those from neurologically healthy controls (n = 591). We demonstrate that APOE ε4 and ε2 carriers have a significantly increased and decreased risk, respectively, of developing Alzheimer's disease (ε4: OR: 4.13, 95% CI: 3.23-5.26, p = 3.67 × 10

25 Article Synthetic mRNAs Drive Highly Efficient iPS Cell Differentiation to Dopaminergic Neurons. 2019

Xue, Yingchao / Zhan, Xiping / Sun, Shisheng / Karuppagounder, Senthilkumar S / Xia, Shuli / Dawson, Valina L / Dawson, Ted M / Laterra, John / Zhang, Jianmin / Ying, Mingyao. ·Department of Immunology, Research Center on Pediatric Development and Diseases, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, State Key Laboratory of Medical Molecular Biology, Beijing, People's Republic of China. · Hugo W. Moser Research Institute at Kennedy Krieger, Baltimore, Maryland, USA. · Department of Physiology and Biophysics, Howard University, Washington, District of Columbia, USA. · College of Life Sciences, Northwest University, Xi'an, People's Republic of China. · Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. · Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. · Adrienne Helis Malvin Medical Research Foundation, New Orleans, Louisiana, USA. · Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. · Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. · Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. · Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. ·Stem Cells Transl Med · Pubmed #30387318.

ABSTRACT: Proneural transcription factors (TFs) drive highly efficient differentiation of pluripotent stem cells to lineage-specific neurons. However, current strategies mainly rely on genome-integrating viruses. Here, we used synthetic mRNAs coding two proneural TFs (Atoh1 and Ngn2) to differentiate induced pluripotent stem cells (iPSCs) into midbrain dopaminergic (mDA) neurons. mRNAs coding Atoh1 and Ngn2 with defined phosphosite modifications led to higher and more stable protein expression, and induced more efficient neuron conversion, as compared to mRNAs coding wild-type proteins. Using these two modified mRNAs with morphogens, we established a 5-day protocol that can rapidly generate mDA neurons with >90% purity from normal and Parkinson's disease iPSCs. After in vitro maturation, these mRNA-induced mDA (miDA) neurons recapitulate key biochemical and electrophysiological features of primary mDA neurons and can provide high-content neuron cultures for drug discovery. Proteomic analysis of Atoh1-binding proteins identified the nonmuscle myosin II (NM-II) complex as a new binding partner of nuclear Atoh1. The NM-II complex, commonly known as an ATP-dependent molecular motor, binds more strongly to phosphosite-modified Atoh1 than the wild type. Blebbistatin, an NM-II complex antagonist, and bradykinin, an NM-II complex agonist, inhibited and promoted, respectively, the transcriptional activity of Atoh1 and the efficiency of miDA neuron generation. These findings established the first mRNA-driven strategy for efficient iPSC differentiation to mDA neurons. We further identified the NM-II complex as a positive modulator of Atoh1-driven neuron differentiation. The methodology described here will facilitate the development of mRNA-driven differentiation strategies for generating iPSC-derived progenies widely applicable to disease modeling and cell replacement therapy. Stem Cells Translational Medicine 2019;8:112&12.

Next