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

Swetha Mohan, Paul J. Sampognaro, Andrea R. Argouarch, Jason C. Maynard, Anand Patwardhan, Mackenzie Welch, Emma C. Courtney, Jiasheng Zhang, Amanda Mason, Kathy H. Li, Eric J. Huang, William W. Seeley (+4 others)
2020 unpublished
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
more » ... 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 show increased PGRN processing to granulin F and an increased activity of AEP, in a region-specific manner. 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.
doi:10.21203/ fatcat:focnfqxa7rentikcpge5tgjzge