# Development of Mass Spectrometry Strategies to Decipher Dynamic Lysosomal Dysfunctions in Frontotemporal Dementia

> **NIH NIH R01** · GEORGE WASHINGTON UNIVERSITY · 2023 · $388,272

## Abstract

Lysosomal dysfunctions have been extensively associated with neurodegenerative diseases, but the
molecular mechanisms remain unclear. Mutations in the GRN gene, which lead to the deficiency of
progranulin (PGRN), a lysosomal glycoprotein, cause Frontotemporal dementia (FTD). Loss of PGRN
impairs lysosomal activity, but the precise function of PGRN in lysosomes is unknown. This is, in part, due
to a lack of high-throughput methodologies to identify and quantify proteins involved in the highly dynamic
and sometimes transient lysosomal activities. The long-term goal is to identify druggable pathways and
therapeutic targets for FTD. The overall objectives of this proposal are to 1) develop mass spectrometry
(MS)-based proteomic strategies to characterize spatiotemporal lysosomal interaction, composition, and
degradative function in human Induced pluripotent stem cell (iPSC)-derived neurons and 2) evaluate how
PGRN deficiency impairs dynamic lysosomal activities and phenotypes in human neurons. The central
hypothesis is that loss of progranulin impairs lysosomal interaction and degradative function in human
neurons, which can be determined by a combination of MS-based proteomic strategies and cell biology
approaches. The objectives will be achieved by the following three specific aims: Aim 1: Develop
spatiotemporal lysosomal proximity labeling methods to determine if loss of progranulin impairs dynamic
lysosomal interaction and composition in human neurons. Aim 2: Develop a dynamic SILAC proteomic
method to determine if loss of progranulin alters the turnover rates of proteins that rely on autophagy for
degradation in neurons. Aim 3: Determine if extracellular addition of progranulin can rescue the proteomic
changes and FTD phenotype caused by progranulin deficiency in human neurons. The proposed research
is highly innovative both in technological and biological aspects. It uniquely integrates innovative MS-based
proteomic techniques with the advanced human iPSC-neuron platform and cell biology approaches to
characterize dynamic lysosomal activities and molecular mechanisms underlying FTD. If extracellular
progranulin does rescue the proteomic changes and FTD phenotype, then increasing progranulin levels
can be a very promising therapeutic method to develop disease modifying treatments for FTD.

## Key facts

- **NIH application ID:** 10600015
- **Project number:** 5R01NS121608-03
- **Recipient organization:** GEORGE WASHINGTON UNIVERSITY
- **Principal Investigator:** Ling Hao
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $388,272
- **Award type:** 5
- **Project period:** 2021-04-15 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10600015

## Citation

> US National Institutes of Health, RePORTER application 10600015, Development of Mass Spectrometry Strategies to Decipher Dynamic Lysosomal Dysfunctions in Frontotemporal Dementia (5R01NS121608-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10600015. Licensed CC0.

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