The lysosomal protein cathepsin L is a progranulin protease

Chris W. Lee, Jeannette N. Stankowski, Jeannie Chew, Casey Cook, Ying Wai Lam, Sandra Almeida, Yari Carlomagno, Kwok Fai Lau, Mercedes Prudencio, Fen Biao Gao, Matthew Bogyo, Dennis W Dickson, Leonard Petrucelli

Research output: Contribution to journalArticle

14 Citations (Scopus)

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.

Original languageEnglish (US)
Article number55
JournalMolecular Neurodegeneration
Volume12
Issue number1
DOIs
StatePublished - Jul 25 2017

Fingerprint

Cathepsin L
Frontotemporal Lobar Degeneration
Peptide Hydrolases
Neuronal Ceroid-Lipofuscinoses
Lysosomal Storage Diseases
Neurons
Haploinsufficiency
Cysteine Proteases
HEK293 Cells
Lysosomes
Dementia
Brain
Genes
lysosomal proteins
granulin precursor protein

Keywords

  • Cathepsin L
  • Frontotemporal lobar degeneration
  • Lysosome
  • Neuronal ceroid lipofuscinosis
  • Neutrophil elastase
  • Progranulin

ASJC Scopus subject areas

  • Molecular Biology
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

Cite this

The lysosomal protein cathepsin L is a progranulin protease. / Lee, Chris W.; Stankowski, Jeannette N.; Chew, Jeannie; Cook, Casey; Lam, Ying Wai; Almeida, Sandra; Carlomagno, Yari; Lau, Kwok Fai; Prudencio, Mercedes; Gao, Fen Biao; Bogyo, Matthew; Dickson, Dennis W; Petrucelli, Leonard.

In: Molecular Neurodegeneration, Vol. 12, No. 1, 55, 25.07.2017.

Research output: Contribution to journalArticle

Lee, CW, Stankowski, JN, Chew, J, Cook, C, Lam, YW, Almeida, S, Carlomagno, Y, Lau, KF, Prudencio, M, Gao, FB, Bogyo, M, Dickson, DW & Petrucelli, L 2017, 'The lysosomal protein cathepsin L is a progranulin protease', Molecular Neurodegeneration, vol. 12, no. 1, 55. https://doi.org/10.1186/s13024-017-0196-6
Lee, Chris W. ; Stankowski, Jeannette N. ; Chew, Jeannie ; Cook, Casey ; Lam, Ying Wai ; Almeida, Sandra ; Carlomagno, Yari ; Lau, Kwok Fai ; Prudencio, Mercedes ; Gao, Fen Biao ; Bogyo, Matthew ; Dickson, Dennis W ; Petrucelli, Leonard. / The lysosomal protein cathepsin L is a progranulin protease. In: Molecular Neurodegeneration. 2017 ; Vol. 12, No. 1.
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