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PLoS Genet. 2019 Aug 9;15(8):e1008295. doi: 10.1371/journal.pgen.1008295. eCollection 2019 Aug.

Age- and stress-associated C. elegans granulins impair lysosomal function and induce a compensatory HLH-30/TFEB transcriptional response.

Author information

1
Memory and Aging Center, Department of Neurology, University of California, San Francisco, California, United States of America.
2
Semel Institute for Neuroscience and Human Behavior, Departments of Psychiatry and Biobehavioral Sciences and Neurology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, United States of America.
3
Department of Pharmaceutical Chemistry, University of California, San Francisco, California, United States of America.
4
Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, New York, New York, United States of America.
5
Department of Physiology, University of California, San Francisco, California, United States of America.

Abstract

The progressive failure of protein homeostasis is a hallmark of aging and a common feature in neurodegenerative disease. As the enzymes executing the final stages of autophagy, lysosomal proteases are key contributors to the maintenance of protein homeostasis with age. We previously reported that expression of granulin peptides, the cleavage products of the neurodegenerative disease protein progranulin, enhance the accumulation and toxicity of TAR DNA binding protein 43 (TDP-43) in Caenorhabditis elegans (C. elegans). In this study we show that C. elegans granulins are produced in an age- and stress-dependent manner. Granulins localize to the endolysosomal compartment where they impair lysosomal protease expression and activity. Consequently, protein homeostasis is disrupted, promoting the nuclear translocation of the lysosomal transcription factor HLH-30/TFEB, and prompting cells to activate a compensatory transcriptional program. The three C. elegans granulin peptides exhibited distinct but overlapping functional effects in our assays, which may be due to amino acid composition that results in distinct electrostatic and hydrophobicity profiles. Our results support a model in which granulin production modulates a critical transition between the normal, physiological regulation of protease activity and the impairment of lysosomal function that can occur with age and disease.

Conflict of interest statement

I have read the journal’s policy and the authors of this manuscript have the following competing interests: M.P.J. is a consultant to and shareholder of Schrodinger LLC, which licenses software used in this work.

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