The lysosomal protein cathepsin L is a progranulin protease
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 ... show 3 more
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Abstract
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.
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Mol Neurodegener. 2017 Jul 25;12(1):55. doi: 10.1186/s13024-017-0196-6. Link to article on publisher's site