# Selective autophagy in Parkinson'sdisease

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2020 · $489,726

## Abstract

In Parkinson's disease (PD), not only has macroautophagy been proposed to be a potential therapeutic
target, but its dysfunction has also been implicated in disease pathogenesis both indirectly and directly.
Macroautophagy (MA) is a lysosome-mediated degradation pathway that first sequesters cytosolic constituents
into a transient, multimembranous vesicle known as an autophagosome (AP), and then fuses into the
endolysosomal system for degradation. Although classically known to promote bulk degradation in response to
starvation, MA also promotes the selective turnover of defined substrates in response to different stressors,
such as protein misfolding and mitochondrial damage. These selective MA pathways achieve selectivity using
adaptor proteins which scaffold cargo to the core autophagic machinery and the nascent AP membrane. Two
selective autophagy pathways have been particularly relevant in PD; aggrephagy, the selective degradation of
protein aggregates, and mitophagy, the selective degradation of mitochondria. If selective MA pathways are to
be considered in global therapeutic strategies for the treatment of PD, it is essential that we apply these
questions to the mammalian brain and models of PD. With this in mind, we will use newly created mouse
models and methods to examine and validate mechanistically the relevance of these two pathways on
pathogenesis in mouse models of genetics PD. First, building upon our identification of the selectivity adaptor
for aggrephagy, we will establish the mechanism by which α-synuclein oligomers enter aggrephagy and
whether affecting its degradation might influence the phenotype, with a special emphasis on axonal pathology,
in a series of transgenic models of α-synuclein. Next, building upon our findings that mitochondrial are by far
the most prevalent autophagic cargo in the brain, we will examine the mechanism by which PINK1 and Parkin
might exert their function in the brain. First, we will establish if compensatory changes in macroautophagic
pathways might be responsible for masking the constitutive loss of PINK1 or Parkin in vivo, then use mouse
genetics to establish better the relationship between these two PD genes and selective macroautophagy.

## Key facts

- **NIH application ID:** 9917855
- **Project number:** 5R01NS101663-03
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Ai Yamamoto
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $489,726
- **Award type:** 5
- **Project period:** 2018-07-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9917855

## Citation

> US National Institutes of Health, RePORTER application 9917855, Selective autophagy in Parkinson'sdisease (5R01NS101663-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9917855. Licensed CC0.

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