# Lysosomal Function of Progranulin and Neurodegeneration

> **NIH NIH R01** · CORNELL UNIVERSITY · 2020 · $484,008

## Abstract

PROJECT SUMMARY/ABSTRACT
Mutations in the Progranulin (PGRN) gene have been linked to two distinct neurodegenerative diseases,
frontotemporal lobar degeneration (FTLD) and neuronal ceroid lipofuscinosis (NCL). Accumulating evidence
suggests a critical role of PGRN in the lysosome. However how PGRN regulates lysosomal function and
protects against neurodegeneration remains elusive. We have identified prosaposin (PSAP), the precursor of
saposin peptides essential for lysosomal glycosphingolipid degradation, as a PGRN binding partner. We
further showed that PGRN facilitates PSAP lysosomal trafficking from the extracellular space via the neuronal
trafficking receptor sortilin. We found reduced neuronal levels of PSAP and saposins in PGRN deficient mice
and in FTLD patients due to PGRN mutations. Moreover, we showed that PGRN forms a complex with PSAP
and lysosomal proteases cathepsin B and D. Cathepsin D deficiency has been reported to cause FTLD
related pathology and our preliminary studies showed that impaired PSAP function also leads to FTLD related
phenotypes in mice. Thus we hypothesize that PGRN is critical for proper PSAP and cathepsin B and D
functions and impaired PSAP and cathepsin functions is one key disease mechanism of FTLD-PGRN. To test
this hypothesis, we propose three specific aims. In Aim1, we will examine the role of PGRN in regulating
PSAP function. PSAP trafficking, processing and glycosphingolipid metabolism will be assayed in WT and
PGRN-/- cells and tissues as well as control and FTLD-PGRN patient samples. In Aim2, we will determine the
role of PGRN in cathepsin B and D trafficking and activation by examining WT and PGRN-/- cells and tissues
as well as control and FTLD-PGRN patient samples. In Aim3, we will assay FTLD like phenotypes in mice
with different levels of PSAP or cathepsin B or D to determine whether partial loss of PSAP or cathepsin
function could contribute to FTLD disease progression. Furthermore, PSAP or cathepsin B or D will be
overexpressed via adeno associated viruses (AAV) to determine whether PSAP or cathepsin overexpression
can rescue phenotypes associated with PGRN loss in mice. In summary, these proposed studies will shed
light on how PGRN regulates lysosomal function and provide novel insights into the disease mechanism of
FTLD. We expect the results from our studies to facilitate therapeutic development for FTLD-PGRN as well
other neurodegenerative diseases with a reported role of PGRN, such as Alzheimer’s disease.

## Key facts

- **NIH application ID:** 9913590
- **Project number:** 5R01NS095954-04
- **Recipient organization:** CORNELL UNIVERSITY
- **Principal Investigator:** Fenghua Hu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $484,008
- **Award type:** 5
- **Project period:** 2017-08-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9913590

## Citation

> US National Institutes of Health, RePORTER application 9913590, Lysosomal Function of Progranulin and Neurodegeneration (5R01NS095954-04). Retrieved via AI Analytics 2026-05-29 from https://api.ai-analytics.org/grant/nih/9913590. Licensed CC0.

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