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

Content Provider	Springer Nature : BioMed Central
Author	Mohan, Swetha Sampognaro, Paul J. Argouarch, Andrea R. Maynard, Jason C. Welch, Mackenzie Patwardhan, Anand Courtney, Emma C. Zhang, Jiasheng Mason, Amanda Li, Kathy H. Huang, Eric J. Seeley, William W. Miller, Bruce L. Burlingame, Alma Jacobson, Mathew P. Kao, Aimee W.
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.
Related Links	https://molecularneurodegeneration.biomedcentral.com/counter/pdf/10.1186/s13024-021-00472-1.pdf
Ending Page	18
Page Count	18
Starting Page	1
File Format	HTM / HTML
ISSN	17501326
DOI	10.1186/s13024-021-00472-1
Journal	Molecular Neurodegeneration
Issue Number	1
Volume Number	16
Language	English
Publisher	BioMed Central
Publisher Date	2021-08-03
Access Restriction	Open
Subject Keyword	Neurosciences Neurology Molecular Medicine Progranulin Granulin Frontotemporal lobar degeneration Lysosome Protease pH Asparagine endopeptidase
Content Type	Text
Resource Type	Article
Subject	Neurology (clinical) Molecular Biology Cellular and Molecular Neuroscience
Journal Impact Factor	15.1/2023
5-Year Journal Impact Factor	16.8/2023

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