# Manipulating autophagy in human neurons to determine subtype-specific neurodegenerative disease phenotypes

> **NIH NIH R21** · SLOAN-KETTERING INST CAN RESEARCH · 2020 · $493,900

## Abstract

One of the main challenges in modern societies is the increase in average life span that is associated with an
increase in age-related disorders such as Alzheimer's disease (AD) or Parkinson's disease (PD). Autophagy is
increasingly recognized as a key factor in counteracting age and age-related disorders such as
neurodegeneration. A major hallmark of many neurodegenerative disorders is the accumulation of misfolded
proteins, and the presence of such characteristic protein aggregates in those late-onset neurodegenerative
disorders indicates that protein homeostasis may be overwhelmed. Among the various components of the
proteostasis machinery, only the autophagosome-lysosome system is capable to engulf large protein aggregates
via a process called macroautophagy (herein after called autophagy). A direct experimental link between
autophagy and neurodegeneration was demonstrated by the neuron- and macroglia-specific knockout of
essential core autophagy genes such as ATG5 or ATG7 in the CNS of mice. Those studies demonstrated the
progressive accumulation of ubiquitinated proteins forming inclusion bodies in neurons, followed by neuronal
loss and premature death. Despite the strong evidence linking autophagy to neurodegeneration and aging in
model organisms, there is very limited information about the role of autophagy in authentic, disease-relevant
human neurons.
Here we propose to establish an inducible and reversible human model of autophagy inhibition to test the
hypothesis that autophagy inhibition in specific neuronal lineages will mimic the characteristic aggregation of
proteins observed in the corresponding human neurodegenerative disorders providing a rationale for age-related
sporadic manifestation of disease phenotypes. For this purpose, we will utilize human pluripotent stem cells
(hPSCs) that enable routine access to disease-relevant neurons at high purity and scale including cortical,
midbrain dopaminergic and spinal motoneurons, the key lineages affected in AD, PD and ALS, respectively. We
will assess the impact of autophagy inhibition at sequential stages of differentiation for each neuronal subtype
and determine reversibility. Importantly, we will use unbiased, state-of-the-art proteomics to determine whether
manipulation of autophagy is sufficient to induce proteomic changes that mimic known and potentially novel
neuron subtype-specific processes involved during neurodegeneration in AD, PD and ALS. Finally, we will
address to what extent those changes are reversible and whether we can use this approach to define novel
candidate therapeutic targets that may intervene with disease progression of the neurodegenerative process.

## Key facts

- **NIH application ID:** 9958860
- **Project number:** 1R21NS116545-01
- **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH
- **Principal Investigator:** LORENZ P. STUDER
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $493,900
- **Award type:** 1
- **Project period:** 2020-04-01 → 2021-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9958860

## Citation

> US National Institutes of Health, RePORTER application 9958860, Manipulating autophagy in human neurons to determine subtype-specific neurodegenerative disease phenotypes (1R21NS116545-01). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/9958860. Licensed CC0.

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