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

Molecular Neurodegeneration

Amanda Mason¹  Mackenzie Welch¹  Paul J. Sampognaro¹  Emma C. Courtney¹  Andrea R. Argouarch¹  Aimee W. Kao¹  Swetha Mohan¹  William W. Seeley¹  Bruce L. Miller¹  Anand Patwardhan¹  Eric J. Huang²  Jiasheng Zhang²  Jason C. Maynard³  Kathy H. Li³  Alma Burlingame³  Mathew P. Jacobson³ 

[1] Department of Neurology, Memory and Aging Center, University of California, 94143, San Francisco, California, USA;Department of Pathology, University of California, 94143, San Francisco, California, USA;Department of Pharmaceutical Chemistry, University of California, 94143, San Francisco, California, USA;

关键词: Progranulin;    Granulin;    Frontotemporal lobar degeneration;    Lysosome;    Protease;    pH;    Asparagine endopeptidase;   

DOI  :  10.1186/s13024-021-00472-1

来源: Springer

【 摘 要 】

BackgroundProgranulin 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.ResultsIn 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.ConclusionsThis 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.

【 授权许可】

CC BY