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Parkinson Disease: HELP
Articles by Kim A. Caldwell
Based on 25 articles published since 2010
(Why 25 articles?)
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Between 2010 and 2020, K. A. Caldwell wrote the following 25 articles about Parkinson Disease.
 
+ Citations + Abstracts
1 Review No Country for Old Worms: A Systematic Review of the Application of 2018

Caldwell, Kim A / Thies, Jennifer L / Caldwell, Guy A. ·Department of Biological Sciences, The University of Alabama, Box 870344, Tuscaloosa, AL 35487, USA. kcaldwel@ua.edu. · Departments of Neurology and Neurobiology, Center for Neurodegeneration and Experimental Therapeutics, Nathan Shock Center for Research on the Basic Biology of Aging, University of Alabama at Birmingham School of Medicine, Birmingham, AL 35294, USA. kcaldwel@ua.edu. · Department of Biological Sciences, The University of Alabama, Box 870344, Tuscaloosa, AL 35487, USA. Jthies@crimson.ua.edu. · Department of Biological Sciences, The University of Alabama, Box 870344, Tuscaloosa, AL 35487, USA. gcaldwel@ua.edu. · Departments of Neurology and Neurobiology, Center for Neurodegeneration and Experimental Therapeutics, Nathan Shock Center for Research on the Basic Biology of Aging, University of Alabama at Birmingham School of Medicine, Birmingham, AL 35294, USA. gcaldwel@ua.edu. ·Metabolites · Pubmed #30380609.

ABSTRACT: While progress has been made in discerning genetic associations with Parkinson's disease (PD), identifying elusive environmental contributors necessitates the application of unconventional hypotheses and experimental strategies. Here, we provide an overview of studies that we conducted on a neurotoxic metabolite produced by a species of common soil bacteria,

2 Review C. elegans as a model system to accelerate discovery for Parkinson disease. 2017

Martinez, Bryan A / Caldwell, Kim A / Caldwell, Guy A. ·Department of Biological Sciences, The University of Alabama, Tuscaloosa, AL 35487, USA. · Department of Biological Sciences, The University of Alabama, Tuscaloosa, AL 35487, USA. Electronic address: gcaldwel@ua.edu. ·Curr Opin Genet Dev · Pubmed #28242493.

ABSTRACT: The nematode Caenorhabditis elegans possesses a wealth of opportunities to explore mechanisms which regulate metazoan complexity, basic cellular biology, and neuronal system attributes. Together, these provide a basis for tenable understanding of neurodegenerative disorders such as Parkinson disease (PD) through functional genomic analysis and pharmacological manipulation for the discovery of previously unknown genetic and environmental risk factors. The application of C. elegans has proven prescient in terms of the elucidation of functional effectors of cellular mechanisms underlying PD that translate to mammals. The current state of PD research using C. elegans encompasses defining obscure combinatorial interactions between genes or between genes and the environment, and continues to provide opportunities for the discovery of new therapeutic targets and disease-modifying drugs.

3 Review Lysosomal impairment in Parkinson's disease. 2013

Dehay, Benjamin / Martinez-Vicente, Marta / Caldwell, Guy A / Caldwell, Kim A / Yue, Zhenyue / Cookson, Mark R / Klein, Christine / Vila, Miquel / Bezard, Erwan. ·Institute of Neurodegenerative Diseases, University of Bordeaux Segalen, Centre National de Recherche Scientifique Unité Mixte de Recherche 5293, Bordeaux, France. benjamin.dehay@u-bordeaux2.fr ·Mov Disord · Pubmed #23580333.

ABSTRACT: Impairment of autophagy-lysosomal pathways (ALPs) is increasingly regarded as a major pathogenic event in neurodegenerative diseases, including Parkinson's disease (PD). ALP alterations are observed in sporadic PD brains and in toxic and genetic rodent models of PD-related neurodegeneration. In addition, PD-linked mutations and post-translational modifications of α-synuclein impair its own lysosomal-mediated degradation, thereby contributing to its accumulation and aggregation. Furthermore, other PD-related genes, such as leucine-rich repeat kinase-2 (LRRK2), parkin, and phosphatase and tensin homolog (PTEN)-induced putative kinase 1 (PINK1), have been mechanistically linked to alterations in ALPs. Conversely, mutations in lysosomal-related genes, such as glucocerebrosidase (GBA) and lysosomal type 5 P-type ATPase (ATP13A2), have been linked to PD. New data offer mechanistic molecular evidence for such a connection, unraveling a causal link between lysosomal impairment, α-synuclein accumulation, and neurotoxicity. First, PD-related GBA deficiency/mutations initiate a positive feedback loop in which reduced lysosomal function leads to α-synuclein accumulation, which, in turn, further decreases lysosomal GBA activity by impairing the trafficking of GBA from the endoplasmic reticulum-Golgi to lysosomes, leading to neurodegeneration. Second, PD-related mutations/deficiency in the ATP13A2 gene lead to a general lysosomal impairment characterized by lysosomal membrane instability, impaired lysosomal acidification, decreased processing of lysosomal enzymes, reduced degradation of lysosomal substrates, and diminished clearance of autophagosomes, collectively contributing to α-synuclein accumulation and cell death. According to these new findings, primary lysosomal defects could potentially account for Lewy body formation and neurodegeneration in PD, laying the groundwork for the prospective development of new neuroprotective/disease-modifying therapeutic strategies aimed at restoring lysosomal levels and function.

4 Review C. elegans as a model organism to investigate molecular pathways involved with Parkinson's disease. 2010

Harrington, Adam J / Hamamichi, Shusei / Caldwell, Guy A / Caldwell, Kim A. ·Department of Biological Sciences, The University of Alabama, Tuscaloosa, Alabama 35487-0344, USA. ·Dev Dyn · Pubmed #20108318.

ABSTRACT: Parkinson's disease (PD) is an age-related movement disorder resulting, in part, from selective loss of dopaminergic neurons. Both invertebrate and mammalian models have been developed to study the cellular mechanisms altered during disease progression; nevertheless there are limitations within each model. Mammalian models remain invaluable in studying PD, but are expensive and time consuming. Here, we review genetic and environmental factors associated with PD, and describe how the nematode roundworm, Caenorhabditis elegans, has been used as a model organism for studying various aspects of this neurodegenerative disease. Both genetic and chemical screens have been conducted in C. elegans to identify molecular pathways, proteins, and small molecules that can impact PD pathology. Lastly, we highlight future areas of investigation, in the context of emerging fields in biology, where the nematode can be exploited to provide mechanistic insights and potential strategies to accelerate the path toward possible therapeutic intervention for PD.

5 Article Genetic Defects in Mitochondrial Dynamics in 2019

Hartman, Jessica H / Gonzalez-Hunt, Claudia / Hall, Samantha M / Ryde, Ian T / Caldwell, Kim A / Caldwell, Guy A / Meyer, Joel N. ·Nicholas School of the Environment, Duke University, Durham, NC 27708, USA. · Department of Biological Sciences, The University of Alabama, Tuscaloosa, AL 35487, USA. · Nicholas School of the Environment, Duke University, Durham, NC 27708, USA. joel.meyer@duke.edu. ·Int J Mol Sci · Pubmed #31261893.

ABSTRACT: BACKGROUND: Parkinson's disease (PD) is one of the most common neurodegenerative disorders involving devastating loss of dopaminergic neurons in the substantia nigra. Early steps in PD pathogenesis include mitochondrial dysfunction, and mutations in mitochondrial genes have been linked to familial forms of the disease. However, low penetrance of mutations indicates a likely important role for environmental factors in PD risk through gene by environment interactions. Herein, we study how genetic deficiencies in mitochondrial dynamics processes including fission, fusion, and mitophagy interact with environmental exposures to impact neurodegeneration. METHODS: We utilized the powerful model organism RESULTS: Overall, we found that deficiency in either mitochondrial fusion or fission sensitizes nematodes to UVC exposure (used to model common environmental pollutants) but protects from 6-hydroxydopamine-induced neurodegeneration. By contrast, mitophagy deficiency makes animals more sensitive to these stressors with an interesting exception- CONCLUSIONS: Together, our results support a strong role for gene by environment interactions in driving dopaminergic neurodegeneration and suggest that genetic deficiency in mitochondrial processes can have complex effects on neurodegeneration.

6 Article Distinct functional roles of Vps41-mediated neuroprotection in Alzheimer's and Parkinson's disease models of neurodegeneration. 2018

Griffin, Edward F / Yan, Xiaohui / Caldwell, Kim A / Caldwell, Guy A. ·Department of Biological Sciences, The University of Alabama, Tuscaloosa, AL, USA. · Departments of Neurology and Neurobiology, Center for Neurodegeneration and Experimental Therapeutics, Nathan Shock Center for Research on the Basic Biology of Aging, University of Alabama at Birmingham School of Medicine, Birmingham, AL, USA. ·Hum Mol Genet · Pubmed #30508205.

ABSTRACT: Commonalities and, in some cases, pathological overlap between neurodegenerative diseases have led to speculation that targeting of underlying mechanisms might be of potentially shared therapeutic benefit. Alzheimer's disease is characterized by the formation of plaques, composed primarily of the amyloid-β 1-42 (Aβ) peptide in the brain, resulting in neurodegeneration. Previously, we have shown that overexpression of the lysosomal-trafficking protein, human Vps41 (hVps41), is neuroprotective in a transgenic worm model of Parkinson's disease, wherein progressive dopaminergic neurodegeneration is induced by α-synuclein overexpression. Here, we report the results of a systematic comparison of hVps41-mediated neuroprotection between α-synuclein and Aβ in transgenic nematode models of Caenorhabditis elegans. Our results indicate that an ARF-like GTPase gene product, ARL-8, mitigates endocytic Aβ neurodegeneration in a VPS-41-dependent manner, rather than through RAB-7 and AP3 as with α-synuclein. Furthermore, the neuroprotective effect of ARL-8 or hVps41 appears to be dependent on their colocalization and the activity of ARL-8. Additionally, we demonstrate that the LC3 orthologue, LGG-2, plays a critical role in Aβ toxicity with ARL-8. Further analysis of functional effectors of Aβ protein processing via the lysosomal pathway will assist in the elucidation of the underlying mechanism involving VPS-41-mediated neuroprotection. These results reveal functional distinctions in the intracellular management of neurotoxic proteins that serve to better inform the path for development of therapeutic interventions to halt neurodegeneration.

7 Article Gene-by-environment interactions that disrupt mitochondrial homeostasis cause neurodegeneration in C. elegans Parkinson's models. 2018

Kim, Hanna / Perentis, Rylee J / Caldwell, Guy A / Caldwell, Kim A. ·Department of Biological Sciences, The University of Alabama, Tuscaloosa, AL, 35487, USA. · Departments of Neurobiology, Neurology and Center for Neurodegeneration and Experimental Therapeutics, University of Alabama at Birmingham, Birmingham, AL, 35294, USA. · Department of Biological Sciences, The University of Alabama, Tuscaloosa, AL, 35487, USA. kcaldwel@ua.edu. · Departments of Neurobiology, Neurology and Center for Neurodegeneration and Experimental Therapeutics, University of Alabama at Birmingham, Birmingham, AL, 35294, USA. kcaldwel@ua.edu. ·Cell Death Dis · Pubmed #29748634.

ABSTRACT: Parkinson's disease (PD) is a complex multifactorial disorder where environmental factors interact with genetic susceptibility. Accumulating evidence suggests that mitochondria have a central role in the progression of neurodegeneration in sporadic and/or genetic forms of PD. We previously reported that exposure to a secondary metabolite from the soil bacterium, Streptomyces venezuelae, results in age- and dose-dependent dopaminergic (DA) neurodegeneration in Caenorhabditis elegans and human SH-SY5Y neurons. Initial characterization of this environmental factor indicated that neurodegeneration occurs through a combination of oxidative stress, mitochondrial complex I impairment, and proteostatic disruption. Here we present extended evidence to elucidate the interaction between this bacterial metabolite and mitochondrial dysfunction in the development of DA neurodegeneration. We demonstrate that it causes a time-dependent increase in mitochondrial fragmentation through concomitant changes in the gene expression of mitochondrial fission and fusion components. In particular, the outer mitochondrial membrane fission and fusion genes, drp-1 (a dynamin-related GTPase) and fzo-1 (a mitofusin homolog), are up- and down-regulated, respectively. Additionally, eat-3, an inner mitochondrial membrane fusion component, an OPA1 homolog, is also down regulated. These changes are associated with a metabolite-induced decline in mitochondrial membrane potential and enhanced DA neurodegeneration that is dependent on PINK-1 function. Genetic analysis also indicates an association between the cell death pathway and drp-1 following S. ven exposure. Metabolite-induced neurotoxicity can be suppressed by DA-neuron-specific RNAi knockdown of eat-3. AMPK activation by 5-amino-4-imidazole carboxamide riboside (AICAR) ameliorated metabolite- or PINK-1-induced neurotoxicity; however, it enhanced neurotoxicity under normal conditions. These studies underscore the critical role of mitochondrial dynamics in DA neurodegeneration. Moreover, given the largely undefined environmental components of PD etiology, these results highlight a response to an environmental factor that defines distinct mechanisms underlying a potential contributor to the progressive DA neurodegeneration observed in PD.

8 Article Alpha-synuclein inhibits Snx3-retromer-mediated retrograde recycling of iron transporters in S. cerevisiae and C. elegans models of Parkinson's disease. 2018

Patel, Dhaval / Xu, Chuan / Nagarajan, Sureshbabu / Liu, Zhengchang / Hemphill, Wayne O / Shi, Runhua / Uversky, Vladimir N / Caldwell, Guy A / Caldwell, Kim A / Witt, Stephan N. ·Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, Shreveport, LA 71130, USA. · Department of Biological Sciences, The University of Alabama, Tuscaloosa, AL 35487, USA. · Department of Biological Sciences, The University of New Orleans, New Orleans, LA 70148, USA. · Department of Medicine, Feist-Weiller Cancer Center, Louisiana State University Health Sciences Center, Shreveport, LA 71130, USA. · Department of Molecular Medicine, USF Health Byrd Alzheimer's Research Institute, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA. · Pharmacology, Toxicology and Neuroscience, Louisiana State University Health Sciences Center, Shreveport, LA 71130, USA. ·Hum Mol Genet · Pubmed #29452354.

ABSTRACT: We probed the role of alpha-synuclein (α-syn) in modulating sorting nexin 3 (Snx3)-retromer-mediated recycling of iron transporters in Saccharomyces cerevisiae and Caenorhabditis elegans. In yeast, the membrane-bound heterodimer Fet3/Ftr1 is the high affinity iron importer. Fet3 is a membrane-bound multicopper ferroxidase, whose ferroxidase domain is orthologous to human ceruloplasmin (Cp), that oxidizes external Fe+2 to Fe+3; the Fe+3 ions then channel through the Ftr1 permease into the cell. When the concentration of external iron is low (<1 µM), Fet3/Ftr1 is maintained on the plasma membrane by retrograde endocytic-recycling; whereas, when the concentration of external iron is high (>10 µM), Fet3/Ftr1 is endocytosed and shunted to the vacuole for degradation. We discovered that α-syn expression phenocopies the high iron condition: under the low iron condition (<1 µM), α-syn inhibits Snx3-retromer-mediated recycling of Fet3/Ftr1 and instead shunts Fet3/Ftr1 into the multivesicular body pathway to the vacuole. α-Syn inhibits recycling by blocking the association of Snx3-mCherry molecules with endocytic vesicles, possibly by interfering with the binding of Snx3 to phosphatidylinositol-3-monophosphate. In C. elegans, transgenic worms expressing α-syn exhibit an age-dependent degeneration of dopaminergic neurons that is partially rescued by the iron chelator desferoxamine. This implies that α-syn-expressing dopaminergic neurons are susceptible to changes in iron neurotoxicity with age, whereby excess iron enhances α-syn-induced neurodegeneration. In vivo genetic analysis indicates that α-syn dysregulates iron homeostasis in worm dopaminergic neurons, possibly by inhibiting SNX-3-mediated recycling of a membrane-bound ortholog of Cp (F21D5.3), the iron exporter ferroportin (FPN1.1), or both.

9 Article The Small GTPase RAC1/CED-10 Is Essential in Maintaining Dopaminergic Neuron Function and Survival Against α-Synuclein-Induced Toxicity. 2018

Kim, Hanna / Calatayud, Carles / Guha, Sanjib / Fernández-Carasa, Irene / Berkowitz, Laura / Carballo-Carbajal, Iria / Ezquerra, Mario / Fernández-Santiago, Rubén / Kapahi, Pankaj / Raya, Ángel / Miranda-Vizuete, Antonio / Lizcano, Jose Miguel / Vila, Miquel / Caldwell, Kim A / Caldwell, Guy A / Consiglio, Antonella / Dalfo, Esther. ·Department of Biological Sciences, The University of Alabama, Tuscaloosa, AL, 35487, USA. · Department of Pathology and Experimental Therapeutics, Bellvitge University Hospital-IDIBELL, 08028, L'Hospitalet de Llobregat, Spain. · Institute of Biomedicine of the University of Barcelona (IBUB), Barcelona, 08908, Spain. · Center of Regenerative Medicine in Barcelona (CMRB), Center for Networked Biomedical Research on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Hospital Duran i Reynals, 08908, L'Hospitalet de Llobregat, Spain. · Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA, 94945, USA. · Neurodegenerative Diseases Research Group, Vall d'Hebron Research Institute-Center for Networked Biomedical Research on Neurodegenerative Diseases (CIBERNED), 08035, Barcelona, Spain. · Laboratory of Parkinson Disease and Other Neurodegenerative Movement Disorders, Department of Neurology: Clinical and Experimental Research, IDIBAPS - Hospital Clínic de Barcelona, 08036, Barcelona, Spain. · Catalan Institution for Research and Advanced Studies (ICREA), 08010, Barcelona, Spain. · Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocío/CSIC/ Universidad de Sevilla, 41013, Sevilla, Spain. · Department of Biochemistry and Molecular Biology, Institut de Neurociències, Faculty of Medicine, M2, Universitat Autònoma de Barcelona (UAB), Bellaterra Campus, Cerdanyola del Vallés, Barcelona, Spain. · Department of Pathology and Experimental Therapeutics, Bellvitge University Hospital-IDIBELL, 08028, L'Hospitalet de Llobregat, Spain. consiglio@ub.edu. · Institute of Biomedicine of the University of Barcelona (IBUB), Barcelona, 08908, Spain. consiglio@ub.edu. · Department of Molecular and Translational Medicine, University of Brescia, Brescia, Spain. consiglio@ub.edu. · Department of Biochemistry and Molecular Biology, Institut de Neurociències, Faculty of Medicine, M2, Universitat Autònoma de Barcelona (UAB), Bellaterra Campus, Cerdanyola del Vallés, Barcelona, Spain. esther.dalfo@uab.cat. · Faculty of Medicine, University of Vic-Central University of Catalonia (UVic-UCC), Can Baumann, 08500, Vic, Spain. esther.dalfo@uab.cat. ·Mol Neurobiol · Pubmed #29429047.

ABSTRACT: Parkinson's disease is associated with intracellular α-synuclein accumulation and ventral midbrain dopaminergic neuronal death in the Substantia Nigra of brain patients. The Rho GTPase pathway, mainly linking surface receptors to the organization of the actin and microtubule cytoskeletons, has been suggested to participate to Parkinson's disease pathogenesis. Nevertheless, its exact contribution remains obscure. To unveil the participation of the Rho GTPase family to the molecular pathogenesis of Parkinson's disease, we first used C elegans to demonstrate the role of the small GTPase RAC1 (ced-10 in the worm) in maintaining dopaminergic function and survival in the presence of alpha-synuclein. In addition, ced-10 mutant worms determined an increase of alpha-synuclein inclusions in comparison to control worms as well as an increase in autophagic vesicles. We then used a human neuroblastoma cells (M17) stably over-expressing alpha-synuclein and found that RAC1 function decreased the amount of amyloidogenic alpha-synuclein. Further, by using dopaminergic neurons derived from patients of familial LRRK2-Parkinson's disease we report that human RAC1 activity is essential in the regulation of dopaminergic cell death, alpha-synuclein accumulation, participates in neurite arborization and modulates autophagy. Thus, we determined for the first time that RAC1/ced-10 participates in Parkinson's disease associated pathogenesis and established RAC1/ced-10 as a new candidate for further investigation of Parkinson's disease associated mechanisms, mainly focused on dopaminergic function and survival against α-synuclein-induced toxicity.

10 Article Dysregulation of the Mitochondrial Unfolded Protein Response Induces Non-Apoptotic Dopaminergic Neurodegeneration in 2017

Martinez, Bryan A / Petersen, Daniel A / Gaeta, Anthony L / Stanley, Samuel P / Caldwell, Guy A / Caldwell, Kim A. ·Department of Biological Sciences, The University of Alabama, Tuscaloosa, Alabama 35487. · Department of Biological Sciences, The University of Alabama, Tuscaloosa, Alabama 35487 kcaldwel@ua.edu. ·J Neurosci · Pubmed #29030433.

ABSTRACT: Due to environmental insult or innate genetic deficiency, protein folding environments of the mitochondrial matrix are prone to dysregulation, prompting the activation of a specific organellar stress-response mechanism, the mitochondrial unfolded protein response (UPR

11 Article NCEH-1 modulates cholesterol metabolism and protects against α-synuclein toxicity in a C. elegans model of Parkinson's disease. 2017

Zhang, Siyuan / Glukhova, Samantha A / Caldwell, Kim A / Caldwell, Guy A. ·Department of Biological Sciences, The University of Alabama, Tuscaloosa, AL 35487, USA. · Departments of Neurology and Neurobiology, Center for Neurodegeneration and Experimental Therapeutics, The University of Alabama School of Medicine at Birmingham, Birmingham, AL 35294, USA. ·Hum Mol Genet · Pubmed #28934392.

ABSTRACT: Parkinson's disease (PD) is an aging-associated neurodegenerative disease affecting millions worldwide. Misfolding, oligomerization and accumulation of the human α-synuclein protein is a key pathological hallmark of PD and is associated with the progressive loss of dopaminergic neurons over the course of aging. Lifespan extension via the suppression of IGF-1/insulin-like signaling (IIS) offers a possibility to retard disease onset through induction of metabolic changes that provide neuroprotection. The nceh-1 gene of Caenorhabditis elegans encodes an ortholog of neutral cholesterol ester hydrolase 1 (NCEH-1), an IIS downstream protein that was identified in a screen as a modulator of α-synuclein accumulation in vivo. The mechanism whereby cholesterol metabolism functionally impacts neurodegeneration induced by α-synuclein is undefined. Here we report that NCEH-1 protects dopaminergic neurons from α-synuclein-dependent neurotoxicity in C. elegans via a mechanism that is independent of lifespan extension. We discovered that the presence of cholesterol, LDLR-mediated cholesterol endocytosis, and cholesterol efflux are all essential to NCEH-1-mediated neuroprotection. In protecting from α-synuclein neurotoxicity, NCEH-1 also stimulates cholesterol-derived neurosteroid formation and lowers cellular reactive oxygen species in mitochondria. Collectively, this study augments our understanding of how cholesterol metabolism can modulate a neuroprotective mechanism that attenuates α-synuclein neurotoxicity, thereby pointing toward regulation of neuronal cholesterol turnover as a potential therapeutic avenue for PD.

12 Article Chemical Compensation of Mitochondrial Phospholipid Depletion in Yeast and Animal Models of Parkinson's Disease. 2016

Wang, Shaoxiao / Zhang, Siyuan / Xu, Chuan / Barron, Addie / Galiano, Floyd / Patel, Dhaval / Lee, Yong Joo / Caldwell, Guy A / Caldwell, Kim A / Witt, Stephan N. ·Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, Shreveport, LA, United States of America. · Department of Biological Sciences, The University of Alabama, Tuscaloosa, AL, United States of America. · Department of Pharmacology, Toxicology and Neuroscience, Louisiana State University Health Sciences Center, Shreveport, LA, United States of America. ·PLoS One · Pubmed #27736935.

ABSTRACT: We have been investigating the role that phosphatidylethanolamine (PE) and phosphatidylcholine (PC) content plays in modulating the solubility of the Parkinson's disease protein alpha-synuclein (α-syn) using Saccharomyces cerevisiae and Caenorhabditis elegans. One enzyme that synthesizes PE is the conserved enzyme phosphatidylserine decarboxylase (Psd1/yeast; PSD-1/worms), which is lodged in the inner mitochondrial membrane. We previously found that decreasing the level of PE due to knockdown of Psd1/psd-1 affects the homeostasis of α-syn in vivo. In S. cerevisiae, the co-occurrence of low PE and α-syn in psd1Δ cells triggers mitochondrial defects, stress in the endoplasmic reticulum, misprocessing of glycosylphosphatidylinositol-anchored proteins, and a 3-fold increase in the level of α-syn. The goal of this study was to identify drugs that rescue this phenotype. We screened the Prestwick library of 1121 Food and Drug Administration-approved drugs using psd1Δ + α-syn cells and identified cyclosporin A, meclofenoxate hydrochloride, and sulfaphenazole as putative protective compounds. The protective activity of these drugs was corroborated using C. elegans in which α-syn is expressed specifically in the dopaminergic neurons, with psd-1 depleted by RNAi. Worm populations were examined for dopaminergic neuron survival following psd-1 knockdown. Exposure to cyclosporine, meclofenoxate, and sulfaphenazole significantly enhanced survival at day 7 in α-syn-expressing worm populations whereby 50-55% of the populations displayed normal neurons, compared to only 10-15% of untreated animals. We also found that all three drugs rescued worms expressing α-syn in dopaminergic neurons that were deficient in the phospholipid cardiolipin following cardiolipin synthase (crls-1) depletion by RNAi. We discuss how these drugs might block α-syn pathology in dopaminergic neurons.

13 Article Phosphatidylethanolamine deficiency disrupts α-synuclein homeostasis in yeast and worm models of Parkinson disease. 2014

Wang, Shaoxiao / Zhang, Siyuan / Liou, Liang-Chun / Ren, Qun / Zhang, Zhaojie / Caldwell, Guy A / Caldwell, Kim A / Witt, Stephan N. ·Departments of Biochemistry and Molecular Biology and. · Department of Biological Sciences, The University of Alabama, Tuscaloosa, AL 35487; and. · Department of Zoology and Physiology, University of Wyoming, Laramie, WY 82071. · Departments of Biochemistry and Molecular Biology and Pharmacology, Toxicology, and Neuroscience, Louisiana State University Health Sciences Center, Shreveport, LA 71130; switt1@lsuhsc.edu. ·Proc Natl Acad Sci U S A · Pubmed #25201965.

ABSTRACT: Phosphatidylserine decarboxylase, which is embedded in the inner mitochondrial membrane, synthesizes phosphatidylethanolamine (PE) and, in some cells, synthesizes the majority of this important phospholipid. Normal levels of PE can decline with age in the brain. Here we used yeast and worms to test the hypothesis that low levels of PE alter the homeostasis of the Parkinson disease-associated protein α-synuclein (α-syn). In yeast, low levels of PE in the phosphatidylserine decarboxylase deletion mutant (psd1Δ) cause decreased respiration, endoplasmic reticulum (ER) stress, a defect in the trafficking of the uracil permease, α-syn accumulation and foci, and a slow growth phenotype. Supplemental ethanolamine (ETA), which can be converted to PE via the Kennedy pathway enzymes in the ER, had no effect on respiration, whereas, in contrast, this metabolite partially eliminated ER stress, decreased α-syn foci formation, and restored growth close to that of wild-type cells. In Caenorhabditis elegans, RNAi depletion of phosphatidylserine decarboxylase in dopaminergic neurons expressing α-syn accelerates neurodegeneration, which supplemental ETA rescues. ETA fails to rescue this degeneration in worms that undergo double RNAi depletion of phosphatidylserine decarboxylase (psd-1) and choline/ETA phosphotransferase (cept-1), which encodes the last enzyme in the CDP-ETA Kennedy pathway. This finding suggests that ETA exerts its protective effect by boosting PE through the Kennedy pathway. Overall, a low level of PE causes ER stress, disrupts vesicle trafficking, and causes α-syn to accumulate; such cells likely die from a combination of ER stress and excessive accumulation of α-syn.

14 Article Calcineurin determines toxic versus beneficial responses to α-synuclein. 2014

Caraveo, Gabriela / Auluck, Pavan K / Whitesell, Luke / Chung, Chee Yeun / Baru, Valeriya / Mosharov, Eugene V / Yan, Xiaohui / Ben-Johny, Manu / Soste, Martin / Picotti, Paola / Kim, Hanna / Caldwell, Kim A / Caldwell, Guy A / Sulzer, David / Yue, David T / Lindquist, Susan. ·Whitehead Institute for Biomedical Research, Cambridge, MA 02142; Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139; · Whitehead Institute for Biomedical Research, Cambridge, MA 02142; Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114; Departments of. · Whitehead Institute for Biomedical Research, Cambridge, MA 02142; · Neurology and. · Department of Biological Sciences, The University of Alabama, Tuscaloosa, AL 35487; · Departments of Biomedical Engineering and Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, MD 21205; and. · Department of Biology, Institute of Biochemistry, Eidgenossische Technische Hochschule Zurich, Zurich CH-8093, Switzerland. · Neurology and Psychiatry, Columbia University Medical Center, New York, NY 10032; · Whitehead Institute for Biomedical Research, Cambridge, MA 02142; Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139; lindquist@wi.mit.edu. ·Proc Natl Acad Sci U S A · Pubmed #25122673.

ABSTRACT: Calcineurin (CN) is a highly conserved Ca(2+)-calmodulin (CaM)-dependent phosphatase that senses Ca(2+) concentrations and transduces that information into cellular responses. Ca(2+) homeostasis is disrupted by α-synuclein (α-syn), a small lipid binding protein whose misfolding and accumulation is a pathological hallmark of several neurodegenerative diseases. We report that α-syn, from yeast to neurons, leads to sustained highly elevated levels of cytoplasmic Ca(2+), thereby activating a CaM-CN cascade that engages substrates that result in toxicity. Surprisingly, complete inhibition of CN also results in toxicity. Limiting the availability of CaM shifts CN's spectrum of substrates toward protective pathways. Modulating CN or CN's substrates with highly selective genetic and pharmacological tools (FK506) does the same. FK506 crosses the blood brain barrier, is well tolerated in humans, and is active in neurons and glia. Thus, a tunable response to CN, which has been conserved for a billion years, can be targeted to rebalance the phosphatase's activities from toxic toward beneficial substrates. These findings have immediate therapeutic implications for synucleinopathies.

15 Article The glycolytic enzyme, GPI, is a functionally conserved modifier of dopaminergic neurodegeneration in Parkinson's models. 2014

Knight, Adam L / Yan, Xiaohui / Hamamichi, Shusei / Ajjuri, Rami R / Mazzulli, Joseph R / Zhang, Mike W / Daigle, J Gavin / Zhang, Siyuan / Borom, Akeem R / Roberts, Lindsay R / Lee, S Kyle / DeLeon, Susan M / Viollet-Djelassi, Coralie / Krainc, Dimitri / O'Donnell, Janis M / Caldwell, Kim A / Caldwell, Guy A. ·Department of Biological Sciences, The University of Alabama, Tuscaloosa, AL 35487, USA; The Babraham Institute, Cambridge CB22 3AT, UK. · Department of Biological Sciences, The University of Alabama, Tuscaloosa, AL 35487, USA. · Department of Neurology, Massachusetts General Hospital, Harvard Medical School, MassGeneral Institute for Neurodegenerative Disease, Charlestown, MA 02129, USA. · Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK. · Department of Biological Sciences, The University of Alabama, Tuscaloosa, AL 35487, USA; Departments of Neurology and Neurobiology, Center for Neurodegeneration and Experimental Therapeutics, Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA. · Department of Biological Sciences, The University of Alabama, Tuscaloosa, AL 35487, USA; Departments of Neurology and Neurobiology, Center for Neurodegeneration and Experimental Therapeutics, Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA. Electronic address: gcaldwel@ua.edu. ·Cell Metab · Pubmed #24882066.

ABSTRACT: Neurodegenerative diseases represent an increasing burden in our aging society, yet the underlying metabolic factors influencing onset and progression remain poorly defined. The relationship between impaired IGF-1/insulin-like signaling (IIS) and lifespan extension represents an opportunity to investigate the interface of metabolism with age-associated neurodegeneration. Using data sets of established DAF-2/IIS-signaling components in Caenorhabditis elegans, we conducted systematic RNAi screens in worms to select for daf-2-associated genetic modifiers of α-synuclein misfolding and dopaminergic neurodegeneration, two clinical hallmarks of Parkinson's disease. An outcome of this strategy was the identification of GPI-1/GPI, an enzyme in glucose metabolism, as a daf-2-regulated modifier that acts independent of the downstream cytoprotective transcription factor DAF-16/FOXO to modulate neuroprotection. Subsequent mechanistic analyses using Drosophila and mouse primary neuron cultures further validated the conserved nature of GPI neuroprotection from α-synuclein proteotoxicity. Collectively, these results support glucose metabolism as a conserved functional node at the intersection of proteostasis and neurodegeneration.

16 Article The effects of pdr1, djr1.1 and pink1 loss in manganese-induced toxicity and the role of α-synuclein in C. elegans. 2014

Bornhorst, Julia / Chakraborty, Sudipta / Meyer, Sören / Lohren, Hanna / Brinkhaus, Sigrid Grosse / Knight, Adam L / Caldwell, Kim A / Caldwell, Guy A / Karst, Uwe / Schwerdtle, Tanja / Bowman, Aaron / Aschner, Michael. ·Institute of Food Chemistry, University of Münster, Münster, Germany. ·Metallomics · Pubmed #24452053.

ABSTRACT: Parkinson's disease (PD) is a neurodegenerative brain disorder characterized by selective dopaminergic (DAergic) cell loss that results in overt motor and cognitive deficits. Current treatment options exist to combat PD symptomatology, but are unable to directly target its pathogenesis due to a lack of knowledge concerning its etiology. Several genes have been linked to PD, including three genes associated with an early-onset familial form: parkin, pink1 and dj1. All three genes are implicated in regulating oxidative stress pathways. Another hallmark of PD pathophysiology is Lewy body deposition, associated with the gain-of-function genetic risk factor α-synuclein. The function of α-synuclein is poorly understood, as it shows both neurotoxic and neuroprotective activities in PD. Using the genetically tractable invertebrate Caenorhabditis elegans (C. elegans) model system, the neurotoxic or neuroprotective role of α-synuclein upon acute Mn exposure in the background of mutated pdr1, pink1 or djr1.1 was examined. The pdr1 and djr1.1 mutants showed enhanced Mn accumulation and oxidative stress that was reduced by α-synuclein. Moreover, DAergic neurodegeneration, while unchanged with Mn exposure, returned to wild-type (WT) levels for pdr1, but not djr1.1 mutants expressing α-synuclein. Taken together, this study uncovers a novel, neuroprotective role for WT human α-synuclein in attenuating Mn-induced toxicity in the background of PD-associated genes, and further supports the role of extracellular dopamine in exacerbating Mn neurotoxicity.

17 Article Potentiated Hsp104 variants antagonize diverse proteotoxic misfolding events. 2014

Jackrel, Meredith E / DeSantis, Morgan E / Martinez, Bryan A / Castellano, Laura M / Stewart, Rachel M / Caldwell, Kim A / Caldwell, Guy A / Shorter, James. ·Department of Biochemistry and Biophysics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. · Department of Biochemistry and Biophysics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Biochemistry and Molecular Biophysics Graduate Group, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. · Department of Biological Sciences, University of Alabama, Tuscaloosa, AL 35487, USA. · Department of Biochemistry and Biophysics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Pharmacology Graduate Group, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. · Department of Biochemistry and Biophysics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Biochemistry and Molecular Biophysics Graduate Group, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Pharmacology Graduate Group, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: jshorter@mail.med.upenn.edu. ·Cell · Pubmed #24439375.

ABSTRACT: There are no therapies that reverse the proteotoxic misfolding events that underpin fatal neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and Parkinson's disease (PD). Hsp104, a conserved hexameric AAA+ protein from yeast, solubilizes disordered aggregates and amyloid but has no metazoan homolog and only limited activity against human neurodegenerative disease proteins. Here, we reprogram Hsp104 to rescue TDP-43, FUS, and α-synuclein proteotoxicity by mutating single residues in helix 1, 2, or 3 of the middle domain or the small domain of nucleotide-binding domain 1. Potentiated Hsp104 variants enhance aggregate dissolution, restore proper protein localization, suppress proteotoxicity, and in a C. elegans PD model attenuate dopaminergic neurodegeneration. Potentiating mutations reconfigure how Hsp104 subunits collaborate, desensitize Hsp104 to inhibition, obviate any requirement for Hsp70, and enhance ATPase, translocation, and unfoldase activity. Our work establishes that disease-associated aggregates and amyloid are tractable targets and that enhanced disaggregases can restore proteostasis and mitigate neurodegeneration.

18 Article Mitochondrial dysfunction, oxidative stress, and neurodegeneration elicited by a bacterial metabolite in a C. elegans Parkinson's model. 2014

Ray, A / Martinez, B A / Berkowitz, L A / Caldwell, G A / Caldwell, K A. ·Department of Biological Sciences, The University of Alabama, Tuscaloosa, AL, USA. · 1] Department of Biological Sciences, The University of Alabama, Tuscaloosa, AL, USA [2] Departments of Neurobiology and Neurology, Center for Neurodegeneration and Experimental Therapeutics, University of Alabama at Birmingham, Birmingham, AL, USA. ·Cell Death Dis · Pubmed #24407237.

ABSTRACT: Genetic and idiopathic forms of Parkinson's disease (PD) are characterized by loss of dopamine (DA) neurons and typically the formation of protein inclusions containing the alpha-synuclein (α-syn) protein. Environmental contributors to PD remain largely unresolved but toxins, such as paraquat or rotenone, represent well-studied enhancers of susceptibility. Previously, we reported that a bacterial metabolite produced by Streptomyces venezuelae caused age- and dose-dependent DA neurodegeneration in Caenorhabditis elegans and human SH-SY5Y neurons. We hypothesized that this metabolite from a common soil bacterium could enhance neurodegeneration in combination with PD susceptibility gene mutations or toxicants. Here, we report that exposure to the metabolite in C. elegans DA neurons expressing human α-syn or LRRK2 G2019S exacerbates neurodegeneration. Using the PD toxin models 6-hydroxydopamine and rotenone, we demonstrate that exposure to more than one environmental risk factor has an additive effect in eliciting DA neurodegeneration. Evidence suggests that PD-related toxicants cause mitochondrial dysfunction, thus we examined the impact of the metabolite on mitochondrial activity and oxidative stress. An ex vivo assay of C. elegans extracts revealed that this metabolite causes excessive production of reactive oxygen species. Likewise, enhanced expression of a superoxide dismutase reporter was observed in vivo. The anti-oxidant probucol fully rescued metabolite-induced DA neurodegeneration, as well. Interestingly, the stress-responsive FOXO transcription factor DAF-16 was activated following exposure to the metabolite. Through further mechanistic analysis, we discerned the mitochondrial defects associated with metabolite exposure included adenosine triphosphate impairment and upregulation of the mitochondrial unfolded protein response. Metabolite-induced toxicity in DA neurons was rescued by complex I activators. RNA interference (RNAi) knockdown of mitochondrial complex I subunits resulted in rescue of metabolite-induced toxicity in DA neurons. Taken together, our characterization of cellular responses to the S. venezuelae metabolite indicates that this putative environmental trigger of neurotoxicity may cause cell death, in part, through mitochondrial dysfunction and oxidative stress.

19 Article Yeast reveal a "druggable" Rsp5/Nedd4 network that ameliorates α-synuclein toxicity in neurons. 2013

Tardiff, Daniel F / Jui, Nathan T / Khurana, Vikram / Tambe, Mitali A / Thompson, Michelle L / Chung, Chee Yeun / Kamadurai, Hari B / Kim, Hyoung Tae / Lancaster, Alex K / Caldwell, Kim A / Caldwell, Guy A / Rochet, Jean-Christophe / Buchwald, Stephen L / Lindquist, Susan. ·Whitehead Institute for Biomedical Research (WIBR), Cambridge, MA 02142, USA. ·Science · Pubmed #24158909.

ABSTRACT: α-Synuclein (α-syn) is a small lipid-binding protein implicated in several neurodegenerative diseases, including Parkinson's disease, whose pathobiology is conserved from yeast to man. There are no therapies targeting these underlying cellular pathologies, or indeed those of any major neurodegenerative disease. Using unbiased phenotypic screens as an alternative to target-based approaches, we discovered an N-aryl benzimidazole (NAB) that strongly and selectively protected diverse cell types from α-syn toxicity. Three chemical genetic screens in wild-type yeast cells established that NAB promoted endosomal transport events dependent on the E3 ubiquitin ligase Rsp5/Nedd4. These same steps were perturbed by α-syn itself. Thus, NAB identifies a druggable node in the biology of α-syn that can correct multiple aspects of its underlying pathology, including dysfunctional endosomal and endoplasmic reticulum-to-Golgi vesicle trafficking.

20 Article Valproic acid ameliorates C. elegans dopaminergic neurodegeneration with implications for ERK-MAPK signaling. 2013

Kautu, Bwarenaba B / Carrasquilla, Alejandro / Hicks, Matthew L / Caldwell, Kim A / Caldwell, Guy A. ·Department of Biological Sciences, The University of Alabama, Tuscaloosa, AL 35487, United States. ·Neurosci Lett · Pubmed #23485787.

ABSTRACT: Parkinson's disease (PD) is a currently incurable neurodegenerative disorder that affects the aging population. The loss of dopaminergic neurons in the substantia nigra is one of the pathological features of PD. The precise causes of PD remain unresolved but evidence supports both environmental and genetic contributions. Current efforts for the treatment of PD are directed toward the discovery of compounds that show promise in impeding age-dependent neurodegeneration in PD patients. Alpha-synuclein (α-Syn) is a human protein that is mutated in specific populations of patients with familial PD. Overexpression of α-Syn in animal models of PD replicates key symptoms of PD, including neurodegeneration. Here, we use the nematode Caenorhabditis elegans as a model system, whereby α-Syn toxicity causes dopaminergic neurodegeneration, to test the capacity of valproic acid (VA) to protect neurons. The results of our study showed that treatment of nematodes with moderate concentrations of VA significantly protects dopaminergic neurons against α-Syn toxicity. Consistent with previously established knowledge related to the mechanistic action of VA in the cell, we showed through genetic analysis that the neuroprotection conferred by VA is inhibited by cell-specific depletion of the C. elegans ortholog of the MAP extracellular signal-regulated kinase (ERK), MPK-1, in the dopaminergic neurons. These findings suggest that VA may exert its neuroprotective effect via ERK-MAPK, or alternately could act with MAPK signaling to additively provide dopaminergic neuroprotection.

21 Article Functional analysis of VPS41-mediated neuroprotection in Caenorhabditis elegans and mammalian models of Parkinson's disease. 2012

Harrington, Adam J / Yacoubian, Talene A / Slone, Sunny R / Caldwell, Kim A / Caldwell, Guy A. ·Department of Biological Sciences, The University of Alabama, Tuscaloosa, Alabama 35487, USA. ·J Neurosci · Pubmed #22323726.

ABSTRACT: Disruption of the lysosomal system has emerged as a key cellular pathway in the neurotoxicity of α-synuclein (α-syn) and the progression of Parkinson's disease (PD). A large-scale RNA interference (RNAi) screen using Caenorhabditis elegans identified VPS-41, a multidomain protein involved in lysosomal protein trafficking, as a modifier of α-syn accumulation and dopaminergic neuron degeneration (Hamamichi et al., 2008). Previous studies have shown a conserved neuroprotective function of human VPS41 (hVPS41) against PD-relevant toxins in mammalian cells and C. elegans neurons (Ruan et al., 2010). Here, we report that both the AP-3 (heterotetrameric adaptor protein complex) interaction domain and clathrin heavy-chain repeat domain are required for protecting C. elegans dopaminergic neurons from α-syn-induced neurodegeneration, as well as to prevent α-syn inclusion formation in an H4 human neuroglioma cell model. Using mutant C. elegans and neuron-specific RNAi, we revealed that hVPS41 requires both a functional AP-3 (heterotetrameric adaptor protein complex) and HOPS (homotypic fusion and vacuole protein sorting)-tethering complex to elicit neuroprotection. Interestingly, two nonsynonymous single-nucleotide polymorphisms found within the AP-3 interacting domain of hVPS41 attenuated the neuroprotective property, suggestive of putative susceptibility factors for PD. Furthermore, we observed a decrease in α-syn protein level when hVPS41 was overexpressed in human neuroglioma cells. Thus, the neuroprotective capacity of hVPS41 may be a consequence of enhanced clearance of misfolded and aggregated proteins, including toxic α-syn species. These data reveal the importance of lysosomal trafficking in maintaining cellular homeostasis in the presence of enhanced α-syn expression and toxicity. Our results support hVPS41 as a potential novel therapeutic target for the treatment of synucleinopathies like PD.

22 Article Modeling dopamine neuron degeneration in Caenorhabditis elegans. 2011

Tucci, Michelle L / Harrington, Adam J / Caldwell, Guy A / Caldwell, Kim A. ·Department of Biological Sciences, The University of Alabama, Tuscaloosa, AL, USA. ·Methods Mol Biol · Pubmed #21913098.

ABSTRACT: Ongoing investigations into causes and cures for human movement disorders are important toward the elucidation of diseases, such as Parkinson's disease (PD). The use of animal model systems can provide links to susceptibility factors as well as therapeutic interventions. In this regard, the nematode roundworm, Caenorhabditis elegans, is ideal for age-dependent neurodegenerative disease studies. It is genetically tractable, has a short life span, and a well-defined nervous system. Fluorescent markers, like GFP, are readily visualized in C. elegans as it is a transparent organism; thus the nervous system, and factors that alter the viability of neurons, can be directly examined in vivo. Through expression of the human disease protein, alpha-synuclein, in the worm dopamine neurons, neurodegeneration is observed in an age-dependent manner. Furthermore, application of a dopamine neurotoxin, 6-hydroxy-dopamine, provides another independent model of PD. Described herein are techniques for C. elegans transformation to evaluate candidate neuroprotective gene targets, integration of the extrachromosomal arrays, genetic crosses, and methods for dopamine neuron analysis that are applicable to both types of neurotoxicity. These techniques can be exploited to assess both chemical and genetic modifiers of toxicity, providing additional avenues to advance PD-related discoveries.

23 Article Inhibitors of LRRK2 kinase attenuate neurodegeneration and Parkinson-like phenotypes in Caenorhabditis elegans and Drosophila Parkinson's disease models. 2011

Liu, Zhaohui / Hamamichi, Shusei / Lee, Byoung Dae / Yang, Dejun / Ray, Arpita / Caldwell, Guy A / Caldwell, Kim A / Dawson, Ted M / Smith, Wanli W / Dawson, Valina L. ·Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 Penn Street, Baltimore, MD 21201, USA. ·Hum Mol Genet · Pubmed #21768216.

ABSTRACT: Mutations in leucine-rich repeat kinase 2 (LRRK2) have been identified as a genetic cause of familial Parkinson's disease (PD) and have also been found in the more common sporadic form of PD, thus positioning LRRK2 as important in the pathogenesis of PD. Biochemical studies of the disease-causing mutants of LRRK2 implicates an enhancement of kinase activity as the basis of neuronal toxicity and thus possibly the pathogenesis of PD due to LRRK2 mutations. Previously, a chemical library screen identified inhibitors of LRRK2 kinase activity. Here, two of these inhibitors, GW5074 and sorafenib, are shown to protect against G2019S LRRK2-induced neurodegeneration in vivo in Caenorhabditis elegans and in Drosophila. These findings indicate that increased kinase activity of LRRK2 is neurotoxic and that inhibition of LRRK2 activity can have a disease-modifying effect. This suggests that inhibition of LRRK2 holds promise as a treatment for PD.

24 Article Caenorhabditis elegans as a model system for identifying effectors of α-synuclein misfolding and dopaminergic cell death associated with Parkinson's disease. 2011

Harrington, Adam J / Knight, Adam L / Caldwell, Guy A / Caldwell, Kim A. ·Department of Biological Sciences, The University of Alabama, Tuscaloosa, AL 35487, USA. ·Methods · Pubmed #21195766.

ABSTRACT: Protein misfolding and aggregation are key pathological features observed in numerous neurodegenerative diseases, including the misfolding of α-synuclein (α-syn) in Parkinson's disease (PD) and β-amyloid in Alzheimer's disease. While this phenomenon is widely observed, the etiology and progression of these diseases is not fully understood. Furthermore, there is a lack of therapeutic treatments directed at halting the progression and neurodegeneration associated with these diseases. This demands a need for an inexpensive, easy to manipulate multicellular organism to conduct both genetic and chemical screens within to identify factors that may play a pivotal role in the pathology of these diseases. Herein, we describe methodology involved in identifying genetic modifiers of α-syn misfolding and toxicity in the nematode roundworm, Caenorhabditis elegans. Transgenic nematodes engineered to express human α-syn in the body wall muscles or dopaminergic (DA) neurons result in formation of cytoplasmic puncta or DA neurodegeneration, respectively. Using these models, we describe the use of RNA interference (RNAi) and transgenic gene expression to functionally elucidate potential therapeutic gene targets that alter α-syn misfolding and DA neurotoxicity.

25 Article Differential neuroprotective effects of 14-3-3 proteins in models of Parkinson's disease. 2010

Yacoubian, T A / Slone, S R / Harrington, A J / Hamamichi, S / Schieltz, J M / Caldwell, K A / Caldwell, G A / Standaert, D G. ·Center for Neurodegeneration and Experimental Therapeutics, Department of Neurology, University of Alabama at Birmingham, Birmingham, AL 35294, USA. tyacoub@uab.edu ·Cell Death Dis · Pubmed #21152247.

ABSTRACT: 14-3-3 proteins are important negative regulators of cell death pathways. Recent studies have revealed alterations in 14-3-3s in Parkinson's disease (PD) and the ability of 14-3-3s to interact with alpha-synuclein (α-syn), a protein central to PD pathophysiology. In a transgenic α-syn mouse model, we found reduced expression of 14-3-3θ, ε, and γ. These same isoforms prevent α-syn inclusion formation in an H4 neuroglioma cell model. Using dopaminergic cell lines stably overexpressing each 14-3-3 isoform, we found that overexpression of 14-3-3θ, ε, or γ led to resistance to both rotenone and 1-methyl-4-phenylpyridinium (MPP(+)), while other isoforms were not protective against both toxins. Inhibition of a single protective isoform, 14-3-3θ, by shRNA did not increase vulnerability to neurotoxic injury, but toxicity was enhanced by broad-based inhibition of 14-3-3 action with the peptide inhibitor difopein. Using a transgenic C. elegans model of PD, we confirmed the ability of both human 14-3-3θ and a C. elegans 14-3-3 homolog (ftt-2) to protect dopaminergic neurons from α-syn toxicity. Collectively, these data show a strong neuroprotective effect of enhanced 14-3-3 expression - particularly of the 14-3-3θ, ε, and γ isoforms - in multiple cellular and animal models of PD, and point to the potential value of these proteins in the development of neuroprotective therapies for human PD.