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.
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.
|Wani, Willayat Y; Chatham, John C; Darley-Usmar, Victor et al. (2016) O-GlcNAcylation and neurodegeneration. Brain Res Bull :|
|Redmann, Matthew; Benavides, Gloria A; Berryhill, Taylor F et al. (2016) Inhibition of autophagy with bafilomycin and chloroquine decreases mitochondrial quality and bioenergetic function in primary neurons. Redox Biol 11:73-81|
|Redmann, Matthew; Darley-Usmar, Victor; Zhang, Jianhua (2016) The Role of Autophagy, Mitophagy and Lysosomal Functions in Modulating Bioenergetics and Survival in the Context of Redox and Proteotoxic Damage: Implications for Neurodegenerative Diseases. Aging Dis 7:150-62|
|Wani, Willayat Yousuf; Boyer-Guittaut, MichaÃ«l; Dodson, Matthew et al. (2015) Regulation of autophagy by protein post-translational modification. Lab Invest 95:14-25|
|Zhang, Jianhua (2015) Teaching the basics of autophagy and mitophagy to redox biologists--mechanisms and experimental approaches. Redox Biol 4:242-59|
|Dodson, Matthew; Redmann, Matthew; Rajasekaran, Namakkal S et al. (2015) KEAP1-NRF2 signalling and autophagy in protection against oxidative and reductive proteotoxicity. Biochem J 469:347-55|
|Crabtree, Donna; Dodson, Matthew; Ouyang, Xiaosen et al. (2014) Over-expression of an inactive mutant cathepsin D increases endogenous alpha-synuclein and cathepsin B activity in SH-SY5Y cells. J Neurochem 128:950-61|
|Sheshadri, Namratha; Catanzaro, Joseph M; Bott, Alex J et al. (2014) SCCA1/SERPINB3 promotes oncogenesis and epithelial-mesenchymal transition via the unfolded protein response and IL6 signaling. Cancer Res 74:6318-29|
|Chacko, Balu K; Kramer, Philip A; Ravi, Saranya et al. (2014) The Bioenergetic Health Index: a new concept in mitochondrial translational research. Clin Sci (Lond) 127:367-73|
|Giordano, Samantha; Dodson, Matthew; Ravi, Saranya et al. (2014) Bioenergetic adaptation in response to autophagy regulators during rotenone exposure. J Neurochem 131:625-33|
Showing the most recent 10 out of 36 publications