# The autophagy lysosomal pathway: regulation by progranulin and its role in neurodegenerative disease

> **NIH NIH P01** · NORTHWESTERN UNIVERSITY · 2020 · $480,683

## Abstract

PROJECT SUMMARY
Protein misfolding and disruption of normal protein homeostasis play critical roles in many neurodegenerative
diseases, including Alzheimer's disease (AD) and frontotemporal dementia (FTD). Protein dyshomeostasis is
an important contributor to aging, the most important risk factor for neurodegenerative disease. Progranulin
(GRN) is a conserved protein with links to normal aging and neurodegeneration. Haploinsufficiency causes
FTD, nullizygosity causes neuronal ceroid lipofuscinosis—a lysosomal storage disorder, and polymorphisms in
the GRN gene may increase the risk of common neurodegenerative diseases, including AD. We hypothesize
that GRN deficiency leads to neurodegeneration by impairing the autophagy/lysosomal pathway (ALP), a
critical arm of the proteostasis network (PN), and that ALP deficits contribute to neurodegenerative diseases
more broadly. We performed a genome-wide screen to discover modifiers of GRN levels and hits enriched in
the ALP. We found a reciprocal relationship between GRN and the ALP in primary neurons: GRN levels were
regulated by autophagy and GRN deficiency impaired lysosomes and inhibited ALP flux. Interestingly, genetic
modifiers from our screen that raised GRN levels rescued lysosomal and autophagy deficits caused by GRN
deficiency.
 Our project will investigate the mechanistic relationship between ALP function and neurodegeneration and
explore ALP as a therapeutic target. In Aim 1, we will study how GRN deficiency affects the ALP and other PN
components. We will use proteomics, lipidomics, and RNAseq to define how GRN deficiency alters cell and
lyososome physiology. In addition, we will use an innovative high-throughput longitudinal single-cell analysis
platform, robotic microscopy, with biosensors for ALP and other arms of PN to determine how GRN deficiency
affects their function dynamically and in response to stress. In Aim 2, we will investigate how GRN deficiency
and ALP dysfunction lead to accumulation of Tar DNA binding protein 43 (TDP43) and affect the metabolism of
other proteins linked to neurodegenerative disease. In Aim 3, the Kelly and Finkbeiner labs will collaborate to
identify new small molecules to modulate the autophagy pathway. In preliminary studies, novel autophagy
inducers were identified that promote the clearance of several disease-causing proteins (e.g., tau, synuclein,
TDP43 and mutant huntingtin) and mitigate neurodegeneration phenotypes in human neurons differentiated
from iPSCs of patients with ALS and HD. The discovery of new, safe and effective small-molecule autophagy
inducers would be useful research tools and may form the basis for new therapeutic approaches to
neurodegenerative disease.
 This project will synergize with the broader program by providing expertise and novel assays of the ALP,
innovative iPSC models of neurodegenerative disease and new tools to modulate the ALP. Collaboration with
other projects in the program will help this project put ALP in the cont...

## Key facts

- **NIH application ID:** 9962258
- **Project number:** 5P01AG054407-03
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** STEVEN M FINKBEINER
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $480,683
- **Award type:** 5
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9962258

## Citation

> US National Institutes of Health, RePORTER application 9962258, The autophagy lysosomal pathway: regulation by progranulin and its role in neurodegenerative disease (5P01AG054407-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9962258. Licensed CC0.

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