# Lysosomal Function of Progranulin and Neurodegeneration

> **NIH NIH R01** · CORNELL UNIVERSITY · 2024 · $576,449

## Abstract

Lysosomal function of progranulin and neurodegeneration
Mutations in the granulin (GRN) gene, resulting in haploinsufficiency of the progranulin (PGRN) protein, are a
main cause of frontotemporal lobar degeneration (FTLD). PGRN is comprised of 7.5 granulin repeats and
processed into individual granulin peptides in the lysosome. PGRN and granulin peptides are critical for proper
lysosome activities and regulate many microglia mediated functions. However, how granulin peptides function
in the lysosome is still unknown. Using our newly generated antibodies against individual granulins, we have
shown that levels of individual granulin peptides can be differentially regulated. One granulin peptide, granulin
E, interacts with CD68, a lysosomal membrane protein highly expressed in microglia. We have found that loss
of CD68 specifically affects the levels of granulin E but no other granulins and PGRN deficiency leads to
changes in CD68 levels and molecular weight, indicating that granulin E and CD68 regulate each other’s
homeostasis in the lysosome. We have also discovered that PGRN interacts with alpha-N-
acetylgalactosaminidase (NAGA), a lysosomal glycosidase, via the granulin F domain, and regulates NAGA
activities. Based on these preliminary data, we hypothesize that individual granulin peptides have unique
properties and functions in the lysosome through binding to specific lysosome protein(s). Three specific aims
are proposed to further dissect the properties and function of granulin peptides in the lysosome. In Aim1, we
will determine the processing and stability of individual granulin peptides, by measuring the levels and half-
lives of individual granulins vs full length PGRN in neurons vs microglia, the two main cell types that express
PGRN in the brain. Changes in the levels of individual granulins will be assayed during aging and
neurodegeneration. The mechanism by which CD68 regulates the levels of granulin E will be elucidated. In
Aim2, we will dissect the functions of individual granulins in the lysosome. The mechanisms by which granulin
peptides E and F regulate CD68 and NAGA functions will be investigated, respectively. Binding partners for
other granulin peptides will be identified through proteomic screens and characterized. In Aim 3, we will
investigate the role of granulins in maintaining lysosomal membrane integrity and the transcriptional program
involved in microglial activation upon PGRN loss, since we have found that PGRN deficiency leads to impaired
lysosomal membrane integrity and enhanced expression of lysosomal proteins and inflammation markers in
microglia. The proposed studies will shed light on the physiological functions of granulin peptides in the
lysosome and the connection between lysosomal dysfunction and microglial activation. Our work will also
facilitate therapeutic development for FTLD and other devastating neurodegenerative diseases.

## Key facts

- **NIH application ID:** 10807053
- **Project number:** 5R01NS095954-08
- **Recipient organization:** CORNELL UNIVERSITY
- **Principal Investigator:** Fenghua Hu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $576,449
- **Award type:** 5
- **Project period:** 2017-08-01 → 2027-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10807053

## Citation

> US National Institutes of Health, RePORTER application 10807053, Lysosomal Function of Progranulin and Neurodegeneration (5R01NS095954-08). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10807053. Licensed CC0.

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