# Understanding cleaved granulin production, protease inhibition and effects on protein homeostasis

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2020 · $354,200

## Abstract

Despite recent progress, it remains unclear how progranulin deficiency leads to development of
frontotemporal lobar degeneration (FTLD) and contributes to Alzheimer’s Disease (AD). Progranulin is
cleaved into bioactive granulin peptides that functionally oppose the progranulin holoprotein. Many believe
that progranulin haploinsufficiency equally depletes progranulin and granulin levels, yet this has never been
directly measured. Fundamental knowledge gaps also exist regarding proteases that cleave progranulin to
produce granulins, the normal function of these cleaved peptides and consequences of granulins on
protein homeostasis and disease. The long-term goal of this research is to understand how age-related
changes in protein homeostasis affect risk of neurodegenerative diseases like AD and FTLD. The objective
of this application is to understand the production, function and consequences of granulins using C.
elegans, cultured cells and patient-derived biospecimens. The central hypothesis is that age and
physiological stress promote the liberation of granulins in the endolysosomal system, where granulins bind
to and inhibit specific lysosomal proteases, ultimately impairing neuronal protein homeostasis. This
hypothesis is based on extensive preliminary data produced by the applicant that granulin production
increases with age and stress, granulins promote TDP-43 accumulation and enhance its toxicity, and these
cysteine-rich peptides can bind and sterically inhibit the active site of a lysosomal aspartyl protease,
cathepsin D. The rationale for this work is that understanding production and function of both progranulin
and granulins is critical to safely targeting these molecules in the treatment of FTLD and other diseases.
The central hypothesis will be tested through three specific aims: 1) understand the regulated production of
granulins, 2) determine the specificity profile of cathepsin inhibition by granulins, and 3) elucidate the
effects of granulins on protein homeostasis. The proposed research is conceptually innovative because it
seeks to directly implicate age-associated granulin accumulation, rather than or in addition to progranulin
deficiency, as a driving force in neurodegeneration related to progranulin mutations. It is also technically
innovative because of development of a novel fluorescent progranulin cleavage sensor tool, use of a new
set of anti-human granulin antibodies and application of BioLayer Interferometry (BLI) for label-free, real-
time monitoring of granulin/cathepsin interaction kinetics. The proposed research will contribute essential
information about the production, specificity and functional consequences of granulins. This contribution is
significant because it will improve understanding of how progranulin haploinsufficiency leads to FTLD,
provide fundamental new knowledge regarding the normal regulation of lysosomal proteases and lay the
foundation for development of safe progranulin replacement therapies.

## Key facts

- **NIH application ID:** 9839479
- **Project number:** 5R01AG059052-03
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Aimee Kao
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $354,200
- **Award type:** 5
- **Project period:** 2018-04-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9839479

## Citation

> US National Institutes of Health, RePORTER application 9839479, Understanding cleaved granulin production, protease inhibition and effects on protein homeostasis (5R01AG059052-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9839479. Licensed CC0.

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