@article{e2580f2687244cd2a1d28fd909e2ff6c,
title = "The lysosomal protein cathepsin L is a progranulin protease",
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.",
keywords = "Cathepsin L, Frontotemporal lobar degeneration, Lysosome, Neuronal ceroid lipofuscinosis, Neutrophil elastase, Progranulin",
author = "Lee, {Chris W.} and Stankowski, {Jeannette N.} and Jeannie Chew and Cook, {Casey N.} and Lam, {Ying Wai} and Sandra Almeida and Yari Carlomagno and Lau, {Kwok Fai} and Mercedes Prudencio and Gao, {Fen Biao} and Matthew Bogyo and Dickson, {Dennis W.} and Leonard Petrucelli",
note = "Funding Information: We are grateful to all patients who donated samples, and to the NIH centers and programs that made this possible. This work was supported in part by the National Institutes of Health (NIH)/ National Institute of Neurological Disorders and Stroke (NINDS) [R35NS097273 (L.P.), P01NS084974 (L.P.), R01NS088689 (L.P.), R01NS093865 (L.P.)]; National Institute of Aging (NIA) [ADRC 2 P50 AG016574-16 (LP)]; Mayo Clinic Foundation (L.P.); Amyotrophic Lateral Sclerosis Association L.P., S.A.); Robert Packard Center for ALS Research at Johns Hopkins (L.P.); Target ALS (L.P.); Association for Frontotemporal Degeneration (L.P., S.A.); Alzheimer {\textquoteleft}s Association (S.A.). Funding Information: We are extremely grateful to all individuals, and their families, who agreed to donate their brains to research. This work was supported by 5R01NS077402 (L.P). Proteomics data reported in this publication were generated by the Vermont Genetics Network Proteomics Facility, which is supported by an Institutional Development Award (IDeA) from the National Institute of General Medical Sciences of the National Institutes of Health under grant number P20GM103449. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of NIGMS or NIH. We also thank Dr. Adam Lesner (University of Gdansk, Poland) for providing the internally quenched Cat L substrate for testing in our study [39]. We would also like to thank Kris Dickson for her assistance in editing and preparing our manuscript. Publisher Copyright: {\textcopyright} 2017 The Author(s).",
year = "2017",
month = jul,
day = "25",
doi = "10.1186/s13024-017-0196-6",
language = "English (US)",
volume = "12",
journal = "Molecular Neurodegeneration",
issn = "1750-1326",
publisher = "BioMed Central",
number = "1",
}