# The role of ATP13A2/PARK9 in secretion of exosomes and alpha synuclein

> **NIH NIH R37** · NORTHWESTERN UNIVERSITY · 2020 · $645,210

## Abstract

Neurodegenerative disorders are characterized by the accumulation of misfolded aggregated
proteins in neurons. Since neurons are permanently postmitotic, efficient intracellular protein
degradation systems are critically important for normal neuronal function. Recent evidence
suggests that disruption of lysosomal degradation pathways directly contributes to
neurodegeneration in Parkinson's disease and related synucleinopathies. We have previously
shown that loss of function of lysosomal ATPase PARK9 (ATP13A2) leads to zinc
dyshomeostasis, lysosomal dysfunction and a-syn accumulation. In addition, we and other
found that PARK9 localizes to multivesicular endosomes and regulates exosome biogenesis.
Here, we propose to further analyze the physiological role of PARK9 in generation and secretion
of exosomes and how loss of PARK9 function contributes to neuronal dysfunction and
neurodegeneration. First, we will test the hypothesis that PARK9 plays an important role in the
formation of intraluminal vesicles by recruitment of zinc-dependent FYVE proteins to early
endosomes. Second, we will examine if a-syn secretion via exosomes and lysosomal
exocytosis contributes to PARK9-mediated neuronal dysfunction. Finally, we will test the
hypothesis that PARK9 is protective in synucleinopathies by overexpressing PARK9 in mouse
models that accumulate a-synuclein. We will also examine propagation of a-synuclein in
PARK9 knockout and transgenic mice. These findings will also provide further mechanistic
insights into PARK9 loss of function in the context of Kufor-Rakeb syndrome as well as more
general forms of syncleinopathies such as Parkinson's disease (PD), especially in terms of cell-
to-cell transmission of a-syn that has been implicated in the pathogenesis of these disorders.

## Key facts

- **NIH application ID:** 10261844
- **Project number:** 4R37NS096241-05
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** DIMITRI KRAINC
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $645,210
- **Award type:** 4N
- **Project period:** 2016-09-30 → 2021-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10261844

## Citation

> US National Institutes of Health, RePORTER application 10261844, The role of ATP13A2/PARK9 in secretion of exosomes and alpha synuclein (4R37NS096241-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10261844. Licensed CC0.

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