# Endolysosomal trafficking and lipid metabolism defects in FTLD

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2024 · $670,577

## Abstract

PROJECT SUMMARY
 Dominant mutations in the human GRN gene cause haploinsufficiency in Progranulin (PGRN) protein levels
and are a leading cause of frontotemporal lobar degeneration with aggregation of RNA binding protein TDP-43
(FTLD-TDP). In addition, single nucleotide polymorphism (SNP) in GRN has been identified as a risk factor for
AD and Limbic predominant, Age-related TDP-43 Encephalopathy (LATE), a major cause of memory
impairments in patients over 90 years old. Despite the critical role of PGRN in brain aging, however, the exact
mechanism by which PGRN haploinsufficiency promotes neurodegeneration remains poorly understood. By
analyzing aging cohorts of Grn knockout (Grn-/-) and humanized GrnR493X/R493X knockin mice, we have shown that
PGRN-deficient microglia produce more complement proteins and pro-inflammatory cytokines to promote
neuronal cell death and TDP-43 proteinopathy during brain aging. Interestingly, our ongoing work shows that
blocking complement activation and proinflammatory cytokines TNFa and IL-1a does not completely mitigate
neurodegeneration, but rather uncover late-onset microglial pathology characterized by profound accumulation
of lipids in Grn-/-, Grn-/-;C1qa-/-;C3-/-, and Grn-/-;C1qa-/-;Tnf-/-;Il1a-/- microglia. Using lipidomics and subcellular
fractionation, we further show that loss of PGRN causes severe blockade in the endolysosomal trafficking of
lipids in Grn-/- microglia, which interferes with lysosome-mediated degradation of lipid droplets and increased
production of proinflammatory oxidized phospholipids. Together, our results broach the hypothesis that PGRN
deficiency causes profound endolysosomal trafficking defects of lipids in microglia and astrocytes to promote
neuronal vulnerability in neurodegeneration. To test this hypothesis, we propose to (1) delineate the mechanism
of endolysosomal trafficking and secretory autophagy that promote lipid-mediated toxicity in Grn-/- microglia, (2)
characterize the role of lipid-dependent and -independent mechanisms in promoting neurotoxicity in Grn-/-
astrocytes, and (3) delineate the contributions of lipids to glial toxicity in FTLD-GRN using comparative snRNA-
seq, IPSC-derived organoids and postmortem tissues. The proposed parallel human-mouse studies will uncover
the contributions of lipid-mediated toxicity in highly disease vulnerable regions in Grn-/- mice and FTLD-GRN will
uncover critical mechanisms that promote glial pathology and neurodegeneration during brain aging and lead to
novel therapeutic targets for ADRD.

## Key facts

- **NIH application ID:** 10837111
- **Project number:** 5R01AG081452-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Eric J Huang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $670,577
- **Award type:** 5
- **Project period:** 2023-05-15 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10837111

## Citation

> US National Institutes of Health, RePORTER application 10837111, Endolysosomal trafficking and lipid metabolism defects in FTLD (5R01AG081452-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10837111. Licensed CC0.

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