The lysosomal protein cathepsin L is a progranulin protease

Chris W. Lee, Jeannette N. Stankowski, Jeannie Chew, Casey N. 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 journalArticlepeer-review

29 Scopus citations


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
Issue number1
StatePublished - Jul 25 2017


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

ASJC Scopus subject areas

  • Molecular Biology
  • Clinical Neurology
  • Cellular and Molecular Neuroscience


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