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Cited by 49Amyotrophic Lateral Sclerosis ResearchAlzheimer's disease research and treatmentsLysosomal Storage Disorders Research

Processing of progranulin into granulins involves multiple lysosomal proteases and is affected in frontotemporal lobar degeneration

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Mohan, Swetha, Sampognaro, Paul J., Argouarch, Andrea R., Maynard, Jason C., Welch, Mackenzie, Patwardhan, Anand, Courtney, Emma C., Zhang, Jiasheng +8 more·2021·Molecular Neurodegeneration
DOI 10.1186/s13024-021-00472-1PMC PMC8330050

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Abstract

Background: Progranulin loss-of-function mutations are linked to frontotemporal lobar degeneration with TDP-43 positive inclusions (FTLD-TDP- Pgrn ). Progranulin (PGRN) is an intracellular and secreted pro-protein that is proteolytically cleaved into individual granulin peptides, which are increasingly thought to contribute to FTLD-TDP- Pgrn disease pathophysiology. Intracellular PGRN is processed into granulins in the endo-lysosomal compartments. Therefore, to better understand the conversion of intracellular PGRN into granulins, we systematically tested the ability of different classes of endo-lysosomal proteases to process PGRN at a range of pH setpoints. Results: In vitro cleavage assays identified multiple enzymes that can process human PGRN into multi- and single-granulin fragments in a pH-dependent manner. We confirmed the role of cathepsin B and cathepsin L in PGRN processing and showed that these and several previously unidentified lysosomal proteases (cathepsins E, G, K, S and V) are able to process PGRN in distinctive, pH-dependent manners. In addition, we have demonstrated a new role for asparagine endopeptidase (AEP) in processing PGRN, with AEP having the unique ability to liberate granulin F from the pro-protein. Brain tissue from individuals with FTLD-TDP- Pgrn showed increased PGRN processing to granulin F and increased AEP activity in degenerating brain regions but not in regions unaffected by disease. Conclusions: This study demonstrates that multiple lysosomal proteases may work in concert to liberate multi-granulin fragments and granulins. It also implicates both AEP and granulin F in the neurobiology of FTLD-TDP- Pgrn . Modulating progranulin cleavage and granulin production may represent therapeutic strategies for FTLD- Pgrn and other progranulin-related diseases.

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  • GRN mutations exhibit full penetrance for disease by age 80.

    “GRN mutations exhibit full penetrance for disease by age 80.112,113”

    From The lysosome and proteostatic stress at the intersection of pediatric neurological disorders and adult neurodegenerative diseases (2025) · cites this paper as [112]

    The Background (page unavailable) says that progranulin haploinsufficiency leads to adult-onset FTLD, supporting the link between GRN mutations and disease. It does not state that penetrance is complete by age 80; searches for penetrance and that age found no such passage. (LLM, conf=0.85)

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Authors
Mohan, S., Sampognaro, P. J., Argouarch, A. R., Maynard, J. C., Welch, M., Patwardhan, A., Courtney, E. C., Zhang, J., Mason, A., Li, K. H., Huang, E. J., Seeley, W. W., Miller, B. L., Burlingame, A., Jacobson, M. P., & Kao, A. W.
Affiliations
University of California, San Francisco (US)
Corresponding author
Kao, Aimee W.
ORCID
Venue
Molecular Neurodegeneration
Publisher
Springer Science and Business Media LLC
Published
2021-08-03
Volume
16
Issue
1
Pages
51-51
ISSN
1750-1326 (ISSN-L)
DOI
10.1186/s13024-021-00472-1
PMC
PMC8330050
OpenAlex
W3115683357
Cited by
49
References
1
Citations by year
2026: 7 · 2025: 12 · 2024: 8 · 2023: 15 · 2022: 7
FWCI
4.07
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular Neurodegeneration (publishedVersion, cc-by)
  • Research Square (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • eScholarship (California Digital Library) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Institutes of Health (R01NS095257, R01AG059052, P01AG019724, P50AG023501)
  • Paul G. Allen Family Foundation (N/A)
  • Consortium for Frontotemporal Dementia Research (N/A)
  • UCSF Program for Breakthrough Biomedical Research (N/A)
  • Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (N/A)
Topics
  • Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
Keywords
progranulin, lysosomal proteases, cathepsin B, cathepsin L, asparaginyl endopeptidase, pH-dependent cleavage, frontotemporal lobar degeneration, TDP-43, granulin
MeSH terms
Progranulins, Granulins, Cell Line, Humans, Lysosomes, Neurons, Peptide Hydrolases, Frontotemporal Lobar Degeneration

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