The progranulin cleavage product granulin 3 exerts a dominant negative effect on animal fitness

Author:

Wang Austin L12ORCID,Mambou Edwina A12,Kao Aimee W123

Affiliation:

1. Memory and Aging Center , Weill Institute for Neuroscience, Department of Neurology, , San Francisco, CA , United States

2. University of California, San Francisco , Weill Institute for Neuroscience, Department of Neurology, , San Francisco, CA , United States

3. Bakar Aging Research Institute, University of California, San Francisco , San Francisco, CA , United States

Abstract

Abstract Progranulin is an evolutionarily conserved protein that has been implicated in human neurodevelopmental and neurodegenerative diseases. Human progranulin is comprised of multiple cysteine-rich, biologically active granulin peptides. Granulin peptides accumulate with age and stress, however their functional contributions relative to full-length progranulin remain unclear. To address this, we generated C. elegans strains that produced quantifiable levels of both full-length progranulin/PGRN-1 protein and cleaved granulin peptide. Using these strains, we demonstrated that even in the presence of intact PGRN-1, granulin peptides suppressed the activity of the lysosomal aspartyl protease activity, ASP-3/CTSD. Granulin peptides were also dominant over PGRN-1 in compromising animal fitness as measured by progress through development and stress response. Finally, the degradation of human TDP-43 was impaired when the granulin to PGRN-1 ratio was increased, representing a disease-relevant downstream impact of impaired lysosomal function. In summary, these studies suggest that not only absolute progranulin levels, but also the balance between full-length progranulin and its cleavage products, is important in regulating lysosomal biology. Given its relevance in human disease, this suggests that the processing of progranulin into granulins should be considered as part of disease pathobiology and may represent a site of therapeutic intervention.

Funder

National Institutes of Health

Bakar Aging Research Institute

Publisher

Oxford University Press (OUP)

Subject

Genetics (clinical),Genetics,Molecular Biology,General Medicine

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