UCSF

Progranulin is an evolutionarily conserved protein. Insufficient levels have been implicated in frontotemporal lobar degeneration with TDP-43 aggregates. 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 produce measurable levels of progranulin and granulins. Using these strains, we demonstrate that an increase in granulin to progranulin-1 (PGRN-1) ratio suppresses the activity of the lysosomal aspartyl protease activity. This increased granulin to PGRN-1 ratio also compromises animal fitness as measured by progress through development and stress response. Further, this increased ratio impairs the degradation of human TDP43, corroborating the impaired lysosomal function. In summary, these studies suggest that the balance between full length PGRN-1 and its cleavage products is important in regulating the lysosomal biology. Given their importance in neurodegenerative disease, this suggests that the processing of progranulin into granulins may be a site of intervention in therapeutic development.