To maintain health, neurons must clear misfolded or mutant proteins in a timely manner, utilizing several pathways for protein degradation. The autophagic-lysosomal system allows cytosolic proteins to be trafficked into specific organelles where they are degraded by lysosomal proteases. Deficits in autophagy have been implicated in many neurodegenerative disorders including Parkinson disease (PD). Alpha-synuclein, a key protein that aggregates in PD, is degraded by autophagy and mutations in several lysosomal enzymes have been linked to familial forms of Parkinsonism. Recent work has focused on how loss of GBA, the gene encoding lysosomal glucocerebrosidase and deficient in Gaucher's disease, leads to an increased risk of PD. Loss of ATP13A2, a lysosomal ATPase, similarly results in a familial form of Parkinsonism, likely through alterations to autophagy. The objective of this proposal is to determine how loss of lysosomal ATP13A2 results in autophagic deficits and PD pathogenesis. I have developed a novel mouse model of PD in which loss of endogenous Atp13a2 results in age-related motor abnormalities and neuropathology. To better understand the mechanism underlying these deficits, I will test the specific hypothesis that loss of Atp13a2 results in impairment of the autophagic-lysosomal system, which in turn causes protein aggregation, neuronal dysfunction, and motor deficits. I will develop this hypothesis with two aims: 1) Determine ultrastructurally how loss of Atp13a2 alters intermediates in the autophagic-lysosomal system and 2) Determine the sequence and timing of lysosome accumulation and protein aggregation in Atp13a2 null mice.
Under Aim 1, I will use electron microscopy to determine the relative abundance of specific autophagic intermediates in wildtype and Atp13a2 null mice.
Under Aim 2, I will assess Atp13a2 null and wildtype mice at different ages to determine the onset of protein aggregation, lysosomal accumulation, and alpha-synuclein insolubility. The experiments outlined in this proposal are expected to contribute fundamental knowledge to the function of ATP13A2 within the lysosome, as well as how loss of ATP13A2 results in KRD. These results will contribute more broadly to understanding the role of the lysosome in PD pathogenesis.

Public Health Relevance

Parkinson disease is the most common neurodegenerative movement disorder and is linked to defects in protein degradation pathways such as the autophagic-lysosomal pathway. This proposal will test the hypothesis that loss of ATP13A2, a lysosomal protein linked to a rare familial form of PD, will disrupt lysosome function in neurons, leading to protein aggregation and motor abnormalities consistent with Parkinson disease. My results are expected to have valuable insights into the cellular mechanisms of Parkinson disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
1F31NS078817-01A1
Application #
8595655
Study Section
NST-2 Subcommittee (NST)
Program Officer
Sutherland, Margaret L
Project Start
2013-07-01
Project End
2015-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
1
Fiscal Year
2013
Total Cost
$32,832
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Neurology
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109