Department of Neurology
Congenital, Hereditary, and Neonatal Diseases and Abnormalities | Molecular and Cellular Neuroscience | Nervous System Diseases
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.
Cathepsin L, Frontotemporal lobar degeneration, Lysosome, Neuronal ceroid lipofuscinosis, Neutrophil elastase, Progranulin
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© The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
DOI of Published Version
Mol Neurodegener. 2017 Jul 25;12(1):55. doi: 10.1186/s13024-017-0196-6. Link to article on publisher's site
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.; and Petrucelli, Leonard, "The lysosomal protein cathepsin L is a progranulin protease" (2017). Open Access Articles. 3199.
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This work is licensed under a Creative Commons Attribution 4.0 License.