a-synuclein (a-syn) mutations or gene amplification cause a small subset of Parkinson's disease (PD), with Lewy body (LB) formation, neurodegeneration and often an associated dementia. a-syn aggregation in LB is also widespread in sporadic PD and other LB diseases without apparent upregulation of transcription. a-syn overexpression leads to its aggregation and/or neurotoxicity in various animal models. Reduction of a-syn is neuroprotective in animal models. These observations suggest a therapeutic potential of reducing a-syn in treatment of PD and other LB diseases. Our long-term objective is to determine the mechanisms and regulation of a-synucleinopathy in neurodegenerative diseases, and to provide novel and effective treatment strategies. We focused on the lysosomal function in modulating neuronal a-syn aggregation and toxicity, because lysosomes are high capacity organelles responsible for clearance of damaged and aggregated proteins, and are implicated in aging and several neurodegenerative diseases. We found that mice with deficient lysosomal cathepsin D (CD) exhibited significant a-syn accumulation in the brains, indicating a critical role for CD in mediating a-syn metabolism. In vitro we have shown that overexpression of CD reduces a-syn aggregation and protects against a-syn-mediated toxicity. To further establish CD as a therapeutic target against a-synucleinopathy, we will examine its effects in vivo, and define the mechanisms of its action in vitro. We hypothesize that CD protects against a-syn neurotoxicity by increasing autophagic clearance of toxic species of a-syn. We will test this hypothesis by performing experiments with the following aims: 1. Test the hypothesis that CD haploinsufficiency increases sensitivity to a-syn-induced neurotoxicity in vivo. 2. Test the hypothesis that stereotaxic delivery of AAV-CD to the SN attenuates a-syn-mediated neurotoxicity in vivo. 3. Test the hypothesis that neuroprotection by CD is through clearance of a-syn by autophagy. Completion of these studies will determine the effect of partial loss-of-CD in a-syn-induced DA neuron death, and the effect of gain-of-function of CD in neuroprotection in vivo. Furthermore, insights into the potential molecular mechanisms of CD-mediated neuroprotection and the molecular mechanisms and regulation of clearance of aggregation-prone proteins, will be gained that will permit further refinement of CD therapeutic strategies.

Public Health Relevance

a-synuclein mutations or gene amplification cause a small ubset of Parkinson's diseases, and aggregates in other neurodegenerative diseases with a-synucleinopathy and sometimes an associated dementia even in an absence of gene mutation. Our work will determine the function of the autophagy-lysosomal pathway in reducing a-syn level and toxicity, a strategy relevant to improving treatment of PD and other a-synucleinopathies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS064090-02
Application #
8055924
Study Section
Cell Death in Neurodegeneration Study Section (CDIN)
Program Officer
Sutherland, Margaret L
Project Start
2010-04-15
Project End
2015-03-31
Budget Start
2011-04-01
Budget End
2012-03-31
Support Year
2
Fiscal Year
2011
Total Cost
$314,059
Indirect Cost
Name
University of Alabama Birmingham
Department
Pathology
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Redmann, Matthew; Benavides, Gloria A; Wani, Willayat Yousuf et al. (2018) Methods for assessing mitochondrial quality control mechanisms and cellular consequences in cell culture. Redox Biol 17:59-69
Zhang, Jianhua; Culp, Matilda Lillian; Craver, Jason G et al. (2018) Mitochondrial function and autophagy: integrating proteotoxic, redox, and metabolic stress in Parkinson's disease. J Neurochem 144:691-709
Nelson, Michael P; Boutin, Michel; Tse, Tonia E et al. (2018) The lysosomal enzyme alpha-Galactosidase A is deficient in Parkinson's disease brain in association with the pathologic accumulation of alpha-synuclein. Neurobiol Dis 110:68-81
Redmann, Matthew; Benavides, Gloria A; Berryhill, Taylor F et al. (2017) Inhibition of autophagy with bafilomycin and chloroquine decreases mitochondrial quality and bioenergetic function in primary neurons. Redox Biol 11:73-81
Dodson, Matthew; Wani, Willayat Y; Redmann, Matthew et al. (2017) Regulation of autophagy, mitochondrial dynamics, and cellular bioenergetics by 4-hydroxynonenal in primary neurons. Autophagy 13:1828-1840
Parekh, Vrajesh V; Pabbisetty, Sudheer K; Wu, Lan et al. (2017) Autophagy-related protein Vps34 controls the homeostasis and function of antigen cross-presenting CD8?+ dendritic cells. Proc Natl Acad Sci U S A 114:E6371-E6380
Cheng, Shaowu; Wani, Willayat Y; Hottman, David A et al. (2017) Haplodeficiency of Cathepsin D does not affect cerebral amyloidosis and autophagy in APP/PS1 transgenic mice. J Neurochem 142:297-304
Wani, Willayat Y; Chatham, John C; Darley-Usmar, Victor et al. (2017) O-GlcNAcylation and neurodegeneration. Brain Res Bull 133:80-87
Redmann, Matthew; Wani, Willayat Y; Volpicelli-Daley, Laura et al. (2017) Trehalose does not improve neuronal survival on exposure to alpha-synuclein pre-formed fibrils. Redox Biol 11:429-437
Wani, Willayat Y; Ouyang, Xiaosen; Benavides, Gloria A et al. (2017) O-GlcNAc regulation of autophagy and ?-synuclein homeostasis; implications for Parkinson's disease. Mol Brain 10:32

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