The lysosomal protein cathepsin L is a progranulin protease

• Published in: Molecular neurodegeneration Vol. 12; no. 1; p. 55
• Main Authors: Lee, Chris W, Stankowski, Jeannette N, Chew, Jeannie, Cook, Casey N, Lam, Ying-Wai, Almeida, Sandra, Carlomagno, Yari, Lau, Kwok-Fai, Prudencio, Mercedes, Gao, Fen-Biao, Bogyo, Matthew, Dickson, Dennis W, Petrucelli, Leonard
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 25.07.2017; BioMed Central; BMC
• Subjects: Age; Binding sites; Cathepsin L; Cathepsin L - metabolism; Cathepsins; Cells, Cultured; Cloning; Cysteine; Cysteine proteinase; Dementia; Dementia disorders; Development and progression; Frontotemporal dementia; Frontotemporal lobar degeneration; Frontotemporal Lobar Degeneration - metabolism; Genetic aspects; Granulin; Haploinsufficiency; Humans; Intercellular Signaling Peptides and Proteins - metabolism; Intracellular; Lysosomal protein; Lysosome; Lysosomes; Lysosomes - metabolism; Neurodegeneration; Neuronal ceroid lipofuscinosis; Neurons - metabolism; Neutrophil elastase; Neutrophils; Peptides; Physiological aspects; Progranulin; Progranulins; Proteins; Proteins - metabolism; Proteolysis; Short Report; United States; Frontotemporal lobar degeneration; Cathepsin L; Neutrophil elastase; Progranulin; Neuronal ceroid lipofuscinosis; Lysosome
• ISSN: 1750-1326; 1750-1326
• DOI: 10.1186/s13024-017-0196-6

Haploinsufficiency of GRN, the gene encoding progranulin (PGRN), causes frontotemporal lobar degeneration (FTLD), the second most common cause of early-onset dementia. Receptor-mediated lysosomal targeting has been shown to regulate brain PGRN levels, and complete deficiency of PGRN is a direct cause of neuronal ceroid lipofuscinosis (NCL), a lysosomal storage disease. Here we show that the lysosomal cysteine protease cathepsin L (Cat L) can mediate the proteolytic cleavage of intracellular PGRN into poly-granulin and granulin fragments. Further, PGRN and Cat L co-localize in lysosomes of HEK293 cells, iPSC-derived neurons and human cortical neurons from human postmortem tissue. These data identify Cat L as a key intracellular lysosomal PGRN protease, and provides an intriguing new link between lysosomal dysfunction and FTLD.