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Parkinson Disease: HELP
Articles by Dalton James Surmeier
Based on 38 articles published since 2008
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Between 2008 and 2019, D. J. Surmeier wrote the following 38 articles about Parkinson Disease.
 
+ Citations + Abstracts
Pages: 1 · 2
1 Review Striatal synapses, circuits, and Parkinson's disease. 2018

Zhai, Shenyu / Tanimura, Asami / Graves, Steven M / Shen, Weixing / Surmeier, D James. ·Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA. · Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA. Electronic address: j-surmeier@northwestern.edu. ·Curr Opin Neurobiol · Pubmed #28843800.

ABSTRACT: The striatum is a hub in the basal ganglia circuitry controlling goal directed actions and habits. The loss of its dopaminergic (DAergic) innervation in Parkinson's disease (PD) disrupts the ability of the two principal striatal projection systems to respond appropriately to cortical and thalamic signals, resulting in the hypokinetic features of the disease. New tools to study brain circuitry have led to significant advances in our understanding of striatal circuits and how they adapt in PD models. This short review summarizes some of these recent studies and the gaps that remain to be filled.

2 Review Parkinson's Disease Is Not Simply a Prion Disorder. 2017

Surmeier, D James / Obeso, José A / Halliday, Glenda M. ·Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, j-surmeier@northwestern.edu. · CINAC, HM Puerta del Sur, Hospitales de Madrid, Mostoles and CEU-San Pablo University, 28938 Madrid, Spain. · Network Center for Biomedical Research on Neurodegenerative Diseases, Instituto Carlos III, 28029 Madrid, Spain. · Brain and Mind Centre, Sydney Medical School, University of Sydney, Sydney, 2006 New South Wales, Australia, and. · School of Medical Sciences, University of New South Wales and Neuroscience Research Australia, Sydney, 2052 New South Wales, Australia. ·J Neurosci · Pubmed #29021297.

ABSTRACT: The notion that prion-like spreading of misfolded α-synuclein (α-SYN) causes Parkinson's disease (PD) has received a great deal of attention. Although attractive in its simplicity, the hypothesis is difficult to reconcile with postmortem analysis of human brains and connectome-mapping studies. An alternative hypothesis is that PD pathology is governed by regional or cell-autonomous factors. Although these factors provide an explanation for the pattern of neuronal loss in PD, they do not readily explain the apparently staged distribution of Lewy pathology in many PD brains, the feature of the disease that initially motivated the spreading hypothesis by Braak and colleagues. While each hypothesis alone has its shortcomings, a synthesis of the two can explain much of what we know about the etiopathology of PD.

3 Review Past, present, and future of Parkinson's disease: A special essay on the 200th Anniversary of the Shaking Palsy. 2017

Obeso, J A / Stamelou, M / Goetz, C G / Poewe, W / Lang, A E / Weintraub, D / Burn, D / Halliday, G M / Bezard, E / Przedborski, S / Lehericy, S / Brooks, D J / Rothwell, J C / Hallett, M / DeLong, M R / Marras, C / Tanner, C M / Ross, G W / Langston, J W / Klein, C / Bonifati, V / Jankovic, J / Lozano, A M / Deuschl, G / Bergman, H / Tolosa, E / Rodriguez-Violante, M / Fahn, S / Postuma, R B / Berg, D / Marek, K / Standaert, D G / Surmeier, D J / Olanow, C W / Kordower, J H / Calabresi, P / Schapira, A H V / Stoessl, A J. ·HM CINAC, Hospital Universitario HM Puerta del Sur, Mostoles, Madrid, Spain. · Universidad CEU San Pablo, Madrid, Spain. · CIBERNED, Madrid, Spain. · Department of Neurology, Philipps University, Marburg, Germany. · Parkinson's Disease and Movement Disorders Department, HYGEIA Hospital and Attikon Hospital, University of Athens, Athens, Greece. · Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois, USA. · Department of Neurology, Medical University Innsbruck, Innsbruck, Austria. · Morton and Gloria Shulman Movement Disorders Clinic and the Edmond J Safra Program in Parkinson's Disease, Toronto Western Hospital, Toronto, Canada. · Department of Medicine, University of Toronto, Toronto, Canada. · Department of Psychiatry, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA. · Parkinson's Disease and Mental Illness Research, Education and Clinical Centers (PADRECC and MIRECC), Corporal Michael J. Crescenz Veteran's Affairs Medical Center, Philadelphia, Pennsylvania, USA. · Medical Sciences, Newcastle University, Newcastle, UK. · Brain and Mind Centre, Sydney Medical School, The University of Sydney, Sydney, Australia. · School of Medical Sciences, University of New South Wales and Neuroscience Research Australia, Sydney, Australia. · Université de Bordeaux, Institut des Maladies Neurodégénératives, Centre National de la Recherche Scientifique Unité Mixte de Recherche 5293, Institut des Maladies Neurodégénératives, Bordeaux, France. · China Academy of Medical Sciences, Institute of Lab Animal Sciences, Beijing, China. · Departments of Neurology, Pathology, and Cell Biology, the Center for Motor Neuron Biology and Disease, Columbia University, New York, New York, USA. · Columbia Translational Neuroscience Initiative, Columbia University, New York, New York, USA. · Institut du Cerveau et de la Moelle épinière - ICM, Centre de NeuroImagerie de Recherche - CENIR, Sorbonne Universités, UPMC Univ Paris 06, Inserm U1127, CNRS UMR 7225, Paris, France. · Groupe Hospitalier Pitié-Salpêtrière, Paris, France. · Clinical Sciences Department, Newcastle University, Newcastle, UK. · Department of Nuclear Medicine, Aarhus University, Aarhus, Denmark. · Human Neurophysiology, Sobell Department, UCL Institute of Neurology, London, UK. · Human Motor Control Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA. · Department of Neurology, Emory University School of Medicine, Atlanta, Georgia, USA. · Morton and Gloria Shulman Movement Disorders Centre and the Edmond J Safra Program in Parkinson's disease, Toronto Western Hospital, University of Toronto, Toronto, Canada. · Movement Disorders and Neuromodulation Center, Department of Neurology, University of California-San Francisco, San Francisco, California, USA. · Parkinson's Disease Research, Education and Clinical Center, San Francisco Veterans Affairs Medical Center, San Francisco, California, USA. · Veterans Affairs Pacific Islands Health Care System, Honolulu, Hawaii, USA. · Parkinson's Institute, Sunnyvale, California, USA. · Institute of Neurogenetics, University of Luebeck, Luebeck, Germany. · Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands. · Parkinson's Disease Center and Movement Disorders Clinic, Department of Neurology, Baylor College of Medicine, Houston, Texas, USA. · Department of Neurosurgery, Toronto Western Hospital, University of Toronto, Toronto, Canada. · Department of Neurology, Universitätsklinikum Schleswig-Holstein, Christian Albrechts University Kiel, Kiel, Germany. · Department of Medical Neurobiology, Institute of Medical Research Israel-Canada, Jerusalem, Israel. · Edmond and Lily Safra Center for Brain Sciences, The Hebrew University, Jerusalem, Israel. · Department of Neurosurgery, Hadassah University Hospital, Jerusalem, Israel. · Parkinson's Disease and Movement Disorders Unit, Neurology Service, Institut Clínic de Neurociències, Hospital Clínic de Barcelona, Barcelona, Spain. · Department of Medicine, Universitat de Barcelona, IDIBAPS, Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED) Barcelona, Spain. · Movement Disorders Clinic, Clinical Neurodegenerative Research Unit, Mexico City, Mexico. · Instituto Nacional de Neurología y Neurocirugía, Mexico City, Mexico. · Department of Neurology, Columbia University Medical Center, New York, New York, USA. · Department of Neurology, McGill University, Montreal General Hospital, Montreal, Quebec, Canada. · Klinik für Neurologie, UKSH, Campus Kiel, Christian-Albrechts-Universität, Kiel, Germany. · Institute for Neurodegenerative Disorders, New Haven, Connecticut, USA. · Department of Neurology, University of Alabama at Birmingham, Birmingham, Alabama, USA. · Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA. · Departments of Neurology and Neuroscience, Mount Sinai School of Medicine, New York, New York, USA. · Research Center for Brain Repair, Rush University Medical Center, Chicago, Illinois, USA. · Neuroscience Graduate Program, Rush University Medical Center, Chicago, Illinois, USA. · Neurological Clinic, Department of Medicine, Hospital Santa Maria della Misericordia, University of Perugia, Perugia, Italy. · Laboratory of Neurophysiology, Santa Lucia Foundation, IRCCS, Rome, Italy. · University Department of Clinical Neurosciences, UCL Institute of Neurology, University College London, London, UK. · Pacific Parkinson's Research Centre, Division of Neurology & Djavadf Mowafaghian Centre for Brain Health, University of British Columbia, British Columbia, Canada. · Vancouver Coastal Health, Vancouver, British Columbia, Canada. ·Mov Disord · Pubmed #28887905.

ABSTRACT: This article reviews and summarizes 200 years of Parkinson's disease. It comprises a relevant history of Dr. James Parkinson's himself and what he described accurately and what he missed from today's perspective. Parkinson's disease today is understood as a multietiological condition with uncertain etiopathogenesis. Many advances have occurred regarding pathophysiology and symptomatic treatments, but critically important issues are still pending resolution. Among the latter, the need to modify disease progression is undoubtedly a priority. In sum, this multiple-author article, prepared to commemorate the bicentenary of the shaking palsy, provides a historical state-of-the-art account of what has been achieved, the current situation, and how to progress toward resolving Parkinson's disease. © 2017 International Parkinson and Movement Disorder Society.

4 Review Calcium, mitochondrial dysfunction and slowing the progression of Parkinson's disease. 2017

Surmeier, D James / Halliday, Glenda M / Simuni, Tanya. ·Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA; Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA. Electronic address: j-surmeier@northwestern.edu. · Brain and Mind Centre, Sydney Medical School, University of Sydney, 2006, Australia; School of Medical Sciences, University of New South Wales, Neuroscience Research Australia, Sydney 2052, Australia. · Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA. ·Exp Neurol · Pubmed #28780195.

ABSTRACT: Parkinson's disease is characterized by progressively distributed Lewy pathology and neurodegeneration. The motor symptoms of clinical Parkinson's disease (cPD) are unequivocally linked to the degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc). Several features of these neurons appear to make them selectively vulnerable to factors thought to cause cPD, like aging, genetic mutations and environmental toxins. Among these features, Ca

5 Review Selective neuronal vulnerability in Parkinson disease. 2017

Surmeier, D James / Obeso, José A / Halliday, Glenda M. ·Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA. · Centro Integral de Neurociencias A.C. (CINAC), HM Puerta del Sur, Hospitales de Madrid, Mostoles and CEU San Pablo University, 28938 Madrid, Spain. · Network Center for Biomedical Research on Neurodegenerative Diseases (CIBERNED), Instituto Carlos III, 28031 Madrid, Spain. · Brain and Mind Centre, Sydney Medical School, The University of Sydney, Sydney 2006, Australia. · School of Medical Sciences, University of New South Wales and Neuroscience Research Australia, Sydney 2052, Australia. ·Nat Rev Neurosci · Pubmed #28104909.

ABSTRACT: Intracellular α-synuclein (α-syn)-rich protein aggregates called Lewy pathology (LP) and neuronal death are commonly found in the brains of patients with clinical Parkinson disease (cPD). It is widely believed that LP appears early in the disease and spreads in synaptically coupled brain networks, driving neuronal dysfunction and death. However, post-mortem analysis of human brains and connectome-mapping studies show that the pattern of LP in cPD is not consistent with this simple model, arguing that, if LP propagates in cPD, it must be gated by cell- or region-autonomous mechanisms. Moreover, the correlation between LP and neuronal death is weak. In this Review, we briefly discuss the evidence for and against the spreading LP model, as well as evidence that cell-autonomous factors govern both α-syn pathology and neuronal death.

6 Review Calcium and Parkinson's disease. 2017

Surmeier, D James / Schumacker, Paul T / Guzman, Jaime D / Ilijic, Ema / Yang, Ben / Zampese, Enrico. ·Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, 60611, Illinois, USA. Electronic address: j-surmeier@northwestern.edu. · Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, 60611, Illinois, USA. · Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, 60611, Illinois, USA. ·Biochem Biophys Res Commun · Pubmed #27590583.

ABSTRACT: Parkinson's disease (PD) is the second most common neurodegenerative disease in the world. Its causes are poorly understood and there is no proven therapeutic strategy for slowing disease progression. The core motor symptoms of PD are caused by the death of dopaminergic neurons in the substantia nigra pars compacta (SNc). In these neurons, Ca

7 Review Dopaminergic modulation of striatal networks in health and Parkinson's disease. 2014

Surmeier, D James / Graves, Steven M / Shen, Weixing. ·Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA. Electronic address: j-surmeier@northwestern.edu. · Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA. ·Curr Opin Neurobiol · Pubmed #25058111.

ABSTRACT: In the last couple of years, there have been significant advances in our understanding of how dopamine modulates striatal circuits underlying goal-directed behaviors and how therapeutic interventions intended to normalize disordered dopaminergic signaling can go awry. This review summarizes some of the advances in this field with a translational focus on Parkinson's disease.

8 Review Neuronal vulnerability, pathogenesis, and Parkinson's disease. 2013

Sulzer, David / Surmeier, D James. ·Department of Psychiatry, Columbia University, New York, New York, USA. ·Mov Disord · Pubmed #23589357.

ABSTRACT: Although there have been significant advances, pathogenesis in Parkinson's disease (PD) is still poorly understood. Potential clues about pathogenesis that have not been systematically pursued are suggested by the restricted pattern of neuronal pathology in the disease. In addition to dopaminergic neurons in the substantia nigra pars compacta (SNc), a significant number of other central and peripheral neuronal populations exhibit Lewy pathology (LP), phenotypic dysregulation, or frank degeneration in PD patients. Drawing on this literature, there appears to be a small number of risk factors contributing to vulnerability. These include autonomous activity, broad action potentials, low intrinsic calcium buffering capacity, poorly myelinated long highly branched axons and terminal fields, and use of a catecholamine neurotransmitter, often with the catecholamine-derived neuromelanin pigment. Of these phenotypic traits, only the physiological ones appear to provide a reachable therapeutic target at present.

9 Review The pathology roadmap in Parkinson disease. 2013

Surmeier, D James / Sulzer, David. ·Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA. j-surmeier@northwestern.edu ·Prion · Pubmed #23324593.

ABSTRACT: An under-appreciated clue about pathogenesis in Parkinson disease (PD) is the distribution of pathology in the early and middle stages of the disease. This pathological 'roadmap' shows that in addition to dopaminergic neurons in the substantia nigra pars compacta (SNc), a significant number of other central and peripheral neuronal populations exhibit Lewy pathology, phenotypic dysregulation or frank degeneration in PD patients. This spatially distributed, at-risk population of neurons shares a number of features, including autonomously generated activity, broad action potentials, low intrinsic calcium buffering capacity and long, poorly myelinated, highly branched axons. Many, and perhaps all, of these traits add to the metabolic burden in these neurons, suggesting that mitochondrial deficits could drive pathogenesis in PD-in agreement with a large segment of the literature. What is less clear is how this neuronal phenotype might shape the susceptibility to proteostatic dysfunction or to the spread of α-synuclein fibrils deposited in the extracellular space. The review explores the literature on these issues and their translational implications.

10 Review Calcium, bioenergetics, and neuronal vulnerability in Parkinson's disease. 2013

Surmeier, D James / Schumacker, Paul T. ·Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA. j-surmeier@northwestern.edu ·J Biol Chem · Pubmed #23086948.

ABSTRACT: The most distinguishing feature of neurons is their capacity for regenerative electrical activity. This activity imposes a significant mitochondrial burden, especially in neurons that are autonomously active, have broad action potentials, and exhibit prominent Ca(2+) entry. Many of the genetic mutations and toxins associated with Parkinson's disease compromise mitochondrial function, providing a mechanistic explanation for the pattern of neuronal pathology in this disease. Because much of the neuronal mitochondrial burden can be traced to L-type voltage-dependent channels (channels for which there are brain-penetrant antagonists approved for human use), a neuroprotective strategy to reduce this burden is available.

11 Review Neuronal vulnerability, pathogenesis, and Parkinson's disease. 2013

Sulzer, David / Surmeier, D James. ·Department of Psychiatry, Columbia University, New York, New York, USA. ds43@columbia.edu ·Mov Disord · Pubmed #22791686.

ABSTRACT: Although there have been significant advances, pathogenesis in Parkinson's disease (PD) is still poorly understood. Potential clues about pathogenesis that have not been systematically pursued are suggested by the restricted pattern of neuronal pathology in the disease. In addition to dopaminergic neurons in the substantia nigra pars compacta (SNc), a significant number of other central and peripheral neuronal populations exhibit Lewy pathology (LP), phenotypic dysregulation, or frank degeneration in PD patients. Drawing on this literature, there appear to be a small number of risk factors contributing to vulnerability. These include autonomous activity, broad action potentials, low intrinsic calcium-buffering capacity, poorly myelinated long highly branched axons and terminal fields, and use of a monoamine neurotransmitter, often with the catecholamine-derived neuromelanin pigment. Of these phenotypic traits, only the physiological ones appear to provide a reachable therapeutic target at present.

12 Review Physiological phenotype and vulnerability in Parkinson's disease. 2012

Surmeier, D James / Guzman, Jaime N / Sanchez, Javier / Schumacker, Paul T. ·Department of Physiology, Northwestern University, Chicago, Illinois, USA. j-surmeier@northwestern.edu ·Cold Spring Harb Perspect Med · Pubmed #22762023.

ABSTRACT: This review will focus on the principles underlying the hypothesis that neuronal physiological phenotype-how a neuron generates and regulates action potentials-makes a significant contribution to its vulnerability in Parkinson's disease (PD) and aging. A cornerstone of this hypothesis is that the maintenance of ionic gradients underlying excitability can pose a significant energetic burden for neurons, particularly those that have sustained residence times at depolarized membrane potentials, broad action potentials, prominent Ca(2+) entry, and modest intrinsic Ca(2+) buffering capacity. This energetic burden is shouldered in neurons primarily by mitochondria, the sites of cellular respiration. Mitochondrial respiration increases the production of damaging superoxide and other reactive oxygen species (ROS) that have widely been postulated to contribute to cellular aging and PD. Many of the genetic mutations and toxins associated with PD compromise mitochondrial function, providing a mechanistic linkage between known risk factors and cellular physiology that could explain the pattern of pathology in PD. Because much of the mitochondrial burden created by this at-risk phenotype is created by Ca(2+) entry through L-type voltage-dependent channels for which there are antagonists approved for human use, a neuroprotective strategy to reduce this burden is feasible.

13 Review Muscarinic modulation of striatal function and circuitry. 2012

Goldberg, Joshua A / Ding, Jun B / Surmeier, D James. ·Department of Physiology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA. ·Handb Exp Pharmacol · Pubmed #22222701.

ABSTRACT: Striatal cholinergic interneurons are pivotal modulators of the striatal circuitry involved in action selection and decision making. Although nicotinic receptors are important transducers of acetylcholine release in the striatum, muscarinic receptors are more pervasive and have been more thoroughly studied. In this review, the effects of muscarinic receptor signaling on the principal cell types in the striatum and its canonical circuits will be discussed, highlighting new insights into their role in synaptic integration and plasticity. These studies, and those that have identified new circuit elements driven by activation of nicotinic receptors, make it clear that temporally patterned activity in cholinergic interneurons must play an important role in determining the effects on striatal circuitry. These effects could be critical to the response to salient environmental stimuli that serve to direct behavior.

14 Review Thalamic contributions to Basal Ganglia-related behavioral switching and reinforcement. 2011

Smith, Yoland / Surmeier, D James / Redgrave, Peter / Kimura, Minoru. ·Yerkes National Primate Research Center and Department of Neurology, Emory University, Atlanta, Georgia 30329, USA. ysmit01@emory.edu ·J Neurosci · Pubmed #22072662.

ABSTRACT: Although the existence of prominent connections between the intralaminar thalamic nuclei and the basal ganglia has long been established, the limited knowledge of the functional relevance of this network has considerably hampered progress in our understanding of the neural mechanisms by which the thalamostriatal system integrates and regulates the basal ganglia circuitry. In this brief commentary, we will address this gap of knowledge through a discussion of the key points of a symposium entitled "Thalamic Contributions to Basal Ganglia-Related Behavioral Switching and Reinforcement" that will be presented at the 2011 Society for Neuroscience meeting. Recent anatomical and physiological data that support the role of the thalamostriatal system in action selection, attentional shifting, and reinforcement will be discussed. We will also address the possibility that degeneration of the thalamostriatal system could underlie some of the deficits in redirection of attention in response to salient stimuli seen in Parkinson's disease.

15 Review The role of calcium and mitochondrial oxidant stress in the loss of substantia nigra pars compacta dopaminergic neurons in Parkinson's disease. 2011

Surmeier, D J / Guzman, J N / Sanchez-Padilla, J / Schumacker, P T. ·Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA. j-surmeier@northwestern.edu ·Neuroscience · Pubmed #21884755.

ABSTRACT: Parkinson's disease (PD) is the second most common neurodegenerative disease in developed countries. The core motor symptoms are attributable to the degeneration of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNc). Why these neurons succumb in PD is not clear. One potential clue has come from the observation that the engagement of L-type Ca²⁺ channels during autonomous pacemaking elevates the sensitivity of SNc DA neurons to mitochondrial toxins used to create animal models of PD, suggesting that Ca²⁺ entry is a factor in their selective vulnerability. Recent work has shown that this Ca²⁺ entry also elevates mitochondrial oxidant stress and that this stress is exacerbated by deletion of DJ-1, a gene associated with an early onset, recessive form of PD. Epidemiological data also support a linkage between L-type Ca²⁺ channels and the risk of developing PD. This review examines the hypothesis that the primary factor driving neurodegenerative changes in PD is the metabolic stress created by Ca²⁺ entry, particularly in the face of genetic or environmental factors that compromise oxidative defenses or proteostatic competence.

16 Review Modulation of striatal projection systems by dopamine. 2011

Gerfen, Charles R / Surmeier, D James. ·Laboratory of Systems Neuroscience, National Institute of Mental Health, Bethesda, Maryland 20892, USA. gerfenc@mail.nih.gov ·Annu Rev Neurosci · Pubmed #21469956.

ABSTRACT: The basal ganglia are a chain of subcortical nuclei that facilitate action selection. Two striatal projection systems--so-called direct and indirect pathways--form the functional backbone of the basal ganglia circuit. Twenty years ago, investigators proposed that the striatum's ability to use dopamine (DA) rise and fall to control action selection was due to the segregation of D(1) and D(2) DA receptors in direct- and indirect-pathway spiny projection neurons. Although this hypothesis sparked a debate, the evidence that has accumulated since then clearly supports this model. Recent advances in the means of marking neural circuits with optical or molecular reporters have revealed a clear-cut dichotomy between these two cell types at the molecular, anatomical, and physiological levels. The contrast provided by these studies has provided new insights into how the striatum responds to fluctuations in DA signaling and how diseases that alter this signaling change striatal function.

17 Review The origins of oxidant stress in Parkinson's disease and therapeutic strategies. 2011

Surmeier, Dalton James / Guzman, Jaime N / Sanchez-Padilla, Javier / Goldberg, Joshua A. ·Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA. ·Antioxid Redox Signal · Pubmed #20712409.

ABSTRACT: Parkinson's disease (PD) is a major world-wide health problem afflicting millions of the aged population. Factors that act on most or all cell types (pan-cellular factors), particularly genetic mutations and environmental toxins, have dominated public discussions of disease etiology. Although there is compelling evidence supporting an association between disease risk and these factors, the pattern of neuronal pathology and cell loss is difficult to explain without cell-specific factors. This article focuses on recent studies showing that the neurons at greatest risk in PD-substantia nigra pars compacta dopamine neurons-have a distinctive physiological phenotype that could contribute to their vulnerability. The opening of L-type calcium channels during autonomous pacemaking results in sustained calcium entry into the cytoplasm of substantia nigra pars compacta dopamine neurons, resulting in elevated mitochondrial oxidant stress and susceptibility to toxins used to create animal models of PD. This cell-specific stress could increase the negative consequences of pan-cellular factors that broadly challenge either mitochondrial or proteostatic competence. The availability of well-tolerated, orally deliverable antagonists for L-type calcium channels points to a novel neuroprotective strategy that could complement current attempts to boost mitochondrial function in the early stages of the disease.

18 Review Calcium, cellular aging, and selective neuronal vulnerability in Parkinson's disease. 2010

Surmeier, D James / Guzman, Jaime N / Sanchez-Padilla, Javier. ·Department of Physiology, Feinberg School of Medicine, Northwestern University, 303 E. Chicago Ave., Chicago, IL 60611, USA. j-surmeier@northwestern.edu ·Cell Calcium · Pubmed #20053445.

ABSTRACT: Parkinson's disease (PD) is the second most common neurodegenerative disease in developed countries. The core motor symptoms are attributable to the degeneration of dopamine (DA) neurons in the substantia nigra pars compacta (SNc). Why these neurons, and other restricted sets of non-dopamine neuron, succumb in PD is not clear. One potential clue has come from the observation that the engagement of L-type Ca2+ channels during autonomous pacemaking elevates the sensitivity of SNc DA neurons to mitochondrial toxins used to create animal models of PD, suggesting that Ca2+ entry is a factor in their selective vulnerability. Epidemiological data also supports a linkage between L-type Ca2+ channels and the risk of developing PD. This review examines the hypothesis that the primary factor driving neurodegenerative changes in PD is the metabolic stress created by sustained Ca2+ entry, particularly in the face of genetic or environmental factors that compromise oxidative defenses or proteostatic competence.

19 Review Dopamine and synaptic plasticity in dorsal striatal circuits controlling action selection. 2009

Surmeier, D James / Plotkin, Joshua / Shen, Weixing. ·Department of Physiology, Northwestern University, Feinberg School of Medicine, Chicago, IL 60611, USA. ·Curr Opin Neurobiol · Pubmed #19896832.

ABSTRACT: The striatum is thought to play a central role in learning how to choose acts that lead to reward and avoid punishment. Dopamine-dependent modification of striatal synapses in the action selection circuitry has long been thought to be a key step toward this type of learning. The development of new genetic and optical tools has pushed this field forward in the last couple of years, demanding a re-evaluation of models of how experience controls dopamine-dependent synaptic plasticity and how disease states like Parkinson's disease affect the striatal circuitry.

20 Review Calcium homeostasis, selective vulnerability and Parkinson's disease. 2009

Chan, C Savio / Gertler, Tracy S / Surmeier, D James. ·Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA. ·Trends Neurosci · Pubmed #19307031.

ABSTRACT: Parkinson's disease (PD) is a common neurodegenerative disorder of which the core motor symptoms are attributable to the degeneration of dopamine (DA) neurons in the substantia nigra pars compacta (SNc). Recent work has revealed that the engagement of L-type Ca(2+) channels during autonomous pacemaking renders SNc DA neurons susceptible to mitochondrial toxins used to create animal models of PD, indicating that homeostatic Ca(2+) stress could be a determinant of their selective vulnerability. This view is buttressed by the central role of mitochondria and the endoplasmic reticulum (linchpins of current theories about the origins of PD) in Ca(2+) homeostasis. Here, we summarize this evidence and suggest the dual roles had by these organelles could compromise their function, leading to accelerated aging of SNc DA neurons, particularly in the face of genetic or environmental stress. We conclude with a discussion of potential therapeutic strategies for slowing the progression of PD.

21 Review Modeling PD pathogenesis in mice: advantages of a chronic MPTP protocol. 2008

Meredith, Gloria E / Totterdell, Susan / Potashkin, Judith A / Surmeier, D James. ·Department of Cellular and Molecular Pharmacology, Chicago Medical School, Rosalind Franklin University of Medicine and Science, 3333 Green Bay Road, North Chicago, IL 60064, USA. gloria.meredith@rosalindfranklin.edu ·Parkinsonism Relat Disord · Pubmed #18585085.

ABSTRACT: Formidable challenges for Parkinson's disease (PD) research are to understand the processes underlying nigrostriatal degeneration and how to protect dopamine neurons. Fundamental research relies on good animal models that demonstrate the pathological hallmarks and motor deficits of PD. Using a chronic regimen of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and probenecid (MPTP/p) in mice, dopamine cell loss exceeds 60%, extracellular glutamate is elevated, cytoplasmic inclusions are formed and inflammation is chronic. Nevertheless, isradipine, an L-type calcium-channel blocker, attenuates the degeneration. These data support the validity of the MPTP/p model for unravelling the degenerative processes in PD and testing therapies that slow their progress.

22 Clinical Trial Tolerability of isradipine in early Parkinson's disease: a pilot dose escalation study. 2010

Simuni, Tanya / Borushko, Emily / Avram, Michael J / Miskevics, Scott / Martel, Audrey / Zadikoff, C / Videnovic, Aleksandar / Weaver, Frances M / Williams, Karen / Surmeier, D James. ·Department of Neurology, Northwestern University, Feinberg School of Medicine, Chicago, Illinois, USA. tsimuni@nmff.org ·Mov Disord · Pubmed #20818667.

ABSTRACT: Recent data suggests that isradipine, a dihydropyridine calcium channel blocker, is neuroprotective in preclinical models of parkinsonism. Isradipine has not been systematically studied in patients with Parkinson's disease (PD). The aim of this study was to evaluate safety and tolerability of isradipine controlled release (CR) in patients with early PD. Qualified subjects (n = 31) received isradipine CR, titrated from 5 to 20 mg daily dose over 8 weeks as tolerated. Eighty-one percent of subjects completed the study. Tolerability of isradipine CR was dose dependent: 94% for 5 mg dose; 87% for 10 mg; 68% for 15 mg; and 52% for 20 mg. Isradipine had no significant effect on blood pressure or PD motor disability. The two most common reasons for dose reduction were leg edema (7) and dizziness (3). There was no difference in isradipine tolerability between subjects with and without dopaminergic treatment, or with and without hypertension.

23 Article α-Synuclein-Dependent Calcium Entry Underlies Differential Sensitivity of Cultured SN and VTA Dopaminergic Neurons to a Parkinsonian Neurotoxin. 2017

Lieberman, Ori J / Choi, Se Joon / Kanter, Ellen / Saverchenko, Anastasia / Frier, Micah D / Fiore, Giulia M / Wu, Min / Kondapalli, Jyothisri / Zampese, Enrico / Surmeier, D James / Sulzer, David / Mosharov, Eugene V. ·New York State Psychiatric Institute, Columbia University Medical Center, New York, NY 10032. · Department of Psychiatry, Columbia University Medical Center, New York, NY 10032. · Department of Neurology, Columbia University Medical Center, New York, NY 10032. · Department of Physiology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611. · Department of Pharmacology, Columbia University Medical Center, New York, NY 10032. ·eNeuro · Pubmed #29177188.

ABSTRACT: Parkinson's disease (PD) is a debilitating neurodegenerative disease characterized by a loss of dopaminergic neurons in the substantia nigra (SN). Although mitochondrial dysfunction and dysregulated α-synuclein (aSyn) expression are postulated to play a role in PD pathogenesis, it is still debated why neurons of the SN are targeted while neighboring dopaminergic neurons of the ventral tegmental area (VTA) are spared. Using electrochemical and imaging approaches, we investigated metabolic changes in cultured primary mouse midbrain dopaminergic neurons exposed to a parkinsonian neurotoxin, 1-methyl-4-phenylpyridinium (MPP

24 Article Dopamine oxidation mediates mitochondrial and lysosomal dysfunction in Parkinson's disease. 2017

Burbulla, Lena F / Song, Pingping / Mazzulli, Joseph R / Zampese, Enrico / Wong, Yvette C / Jeon, Sohee / Santos, David P / Blanz, Judith / Obermaier, Carolin D / Strojny, Chelsee / Savas, Jeffrey N / Kiskinis, Evangelos / Zhuang, Xiaoxi / Krüger, Rejko / Surmeier, D James / Krainc, Dimitri. ·Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA. · Department of Neurology, Massachusetts General Hospital, Harvard Medical School, MassGeneral Institute for Neurodegeneration, Charlestown, MA 02129, USA. · Department of Physiology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA. · Department for Neurodegenerative Diseases and Hertie-Institute for Clinical Brain Research, University of Tübingen, DZNE, German Centre for Neurodegenerative Diseases, Tübingen, Germany. · Graduate School for Cellular and Molecular Neuroscience, University of Tübingen, Germany. · Clinical and Experimental Neuroscience, Luxembourg Center for Systems Biomedicine, University of Luxembourg, Luxembourg. · Department of Neurobiology, University of Chicago, Chicago, IL 60637, USA. · Centre Hospitalier Luxembourg, Luxembourg. · Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA. dkrainc@nm.org. ·Science · Pubmed #28882997.

ABSTRACT: Mitochondrial and lysosomal dysfunction have been implicated in substantia nigra dopaminergic neurodegeneration in Parkinson's disease (PD), but how these pathways are linked in human neurons remains unclear. Here we studied dopaminergic neurons derived from patients with idiopathic and familial PD. We identified a time-dependent pathological cascade beginning with mitochondrial oxidant stress leading to oxidized dopamine accumulation and ultimately resulting in reduced glucocerebrosidase enzymatic activity, lysosomal dysfunction, and α-synuclein accumulation. This toxic cascade was observed in human, but not in mouse, PD neurons at least in part because of species-specific differences in dopamine metabolism. Increasing dopamine synthesis or α-synuclein amounts in mouse midbrain neurons recapitulated pathological phenotypes observed in human neurons. Thus, dopamine oxidation represents an important link between mitochondrial and lysosomal dysfunction in PD pathogenesis.

25 Article Cryopreservation Maintains Functionality of Human iPSC Dopamine Neurons and Rescues Parkinsonian Phenotypes In Vivo. 2017

Wakeman, Dustin R / Hiller, Benjamin M / Marmion, David J / McMahon, Christopher W / Corbett, Grant T / Mangan, Kile P / Ma, Junyi / Little, Lauren E / Xie, Zhong / Perez-Rosello, Tamara / Guzman, Jaime N / Surmeier, D James / Kordower, Jeffrey H. ·Department of Neurological Sciences, Rush University Medical Center, Chicago, IL 60612, USA. Electronic address: dwakeman@rx-gen.com. · Department of Neurological Sciences, Rush University Medical Center, Chicago, IL 60612, USA. · Cellular Dynamics International: A Fujifilm Company, Madison, WI 53711, USA. · Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA. · Department of Neurological Sciences, Rush University Medical Center, Chicago, IL 60612, USA; The Van Andel Institute, Grand Rapids, MI 49503, USA. Electronic address: jkordowe@rush.edu. ·Stem Cell Reports · Pubmed #28579395.

ABSTRACT: A major challenge for clinical application of pluripotent stem cell therapy for Parkinson's disease (PD) is large-scale manufacturing and cryopreservation of neurons that can be efficiently prepared with minimal manipulation. To address this obstacle, midbrain dopamine neurons were derived from human induced pluripotent stem cells (iPSC-mDA) and cryopreserved in large production lots for biochemical and transplantation studies. Cryopreserved, post-mitotic iPSC-mDA neurons retained high viability with gene, protein, and electrophysiological signatures consistent with midbrain floor-plate lineage. To test therapeutic efficacy, cryopreserved iPSC-mDA neurons were transplanted without subculturing into the 6-OHDA-lesioned rat and MPTP-lesioned non-human-primate models of PD. Grafted neurons retained midbrain lineage with extensive fiber innervation in both rodents and monkeys. Behavioral assessment in 6-OHDA-lesioned rats demonstrated significant reversal in functional deficits up to 6 months post transplantation with reinnervation of the host striatum and no aberrant growth, supporting the translational development of pluripotent cell-based therapies in PD.

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