# Neuronal Autophagy: a Cell-Autonomous Protection Mechanism

> **NIH NIH R01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2020 · $582,987

## Abstract

Our long-term goal is to understand neuroprotective mechanisms of autophagy and identify
therapeutic targets of autophagy to treat neurodegenerative diseases associated with
intraneuronal protein aggregates. The physiological function of autophagy in neuron is to maintain
metabolic homeostasis and serve as quality control through constant degradation. Importantly, the
constitutive autophagy in neurons shows high selectivity, targeting specific protein and organelle
cargo to the lysosomal degradation. However, the molecular mechanism for the selective
autophagy remains poorly characterized in neurons. Increasing evidence shows that selective
autophagy is mediated through a family of proteins called autophagy receptors, which are
characterized by the ability to recognize degradation signals on cargo proteins and also bind
LC3/GABARAP proteins on the forming autophagosome. Our current goal is to understand the
physiological function and selective nature of autophagy in neurons and dissect the molecular
mechanism whereby selective autophagy clears disease related proteins particularly related to
Alzheimer’s disease (AD). AD is characterized pathologically by the extracellular amyloid plaques
and intraneuronal neurofibrillary tau tangles. Recent failures of AD clinical trials show the urgency
to have deeper understanding of the pathogenic pathways and develop novel therapeutic
strategies of AD. Indeed, multiple lines of evidence suggest that basal autophagy prevents the
accumulation of phosphorylated tau (p-tau). Furthermore, our lab and others suggests that
autophagy selectively degrades amyloid β precursor protein (APP) and its metabolites (e.g. C-
terminal fragments or CTFs and Aβ). We hypothesize that autophagy selectively removes toxic
tau species and APP/APP metabolites through specific autophagy receptors. Given increasing
evidence implicating autophagy in controlling the levels of p-Tau, APP and its metabolites, we
propose that targeting selective autophagy pathway offers a novel disease-modifying strategy for
the treatment of AD. We propose the following Aims to test above hypothesis: Aim 1. Determine
the physiological function and the selective nature of autophagy in neurons. Aim 2. Examine the
role for selective autophagy in the regulation of tau homeostasis and tauopathies. Aim 3.
Determine the mechanism for selective autophagy in the clearance of APP and its metabolites.
We seek to establish molecular basis for how selective autophagy regulates the homeostasis of
the two most important AD related proteins, phospho-tau and APP (and its metabolites) in CNS;
our study is expected to provides insight into the pathogenesis of AD and assist in the
development of novel disease-modifying strategy for AD treatment.

## Key facts

- **NIH application ID:** 9844079
- **Project number:** 5R01NS060123-13
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Zhenyu Yue
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $582,987
- **Award type:** 5
- **Project period:** 2008-04-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9844079

## Citation

> US National Institutes of Health, RePORTER application 9844079, Neuronal Autophagy: a Cell-Autonomous Protection Mechanism (5R01NS060123-13). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9844079. Licensed CC0.

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