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 CW, Stankowski JN, Chew J, Cook CN, Lam Y, Almeida S, Carlomagno Y, Lau K, Prudencio M, Gao F, Bogyo M, Dickson DW, Petrucelli L. (2017). The lysosomal protein cathepsin L is a progranulin protease. Open Access Articles. https://doi.org/10.1186/s13024-017-0196-6. Retrieved from https://escholarship.umassmed.edu/oapubs/3199
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This work is licensed under a Creative Commons Attribution 4.0 License.