Holler CJ, Taylor G, Deng Q, Kukar T. Intracellular Proteolysis of Progranulin Generates Stable, Lysosomal Granulins that Are Haploinsufficient in Patients with Frontotemporal Dementia Caused byMutations. eNeuro. 2017 Jul-Aug;4(4) Epub 2017 Aug 18 PubMed.
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The paper from Xiaolai Zhou et al. in Fenghua Hu's lab further supports the hypothesis that intracellular progranulin is processed into mature granulins in the lysosomal pathway. They demonstrate that modulation of cathepsin expression or pharmacologic inhibition of the lysosome affect progranulin processing into granulins, which nicely complements our data as well as the data from the Lee/Petrucelli paper. They also demonstrate that in addition to SORT1, the PSAP pathway is important for trafficking PGRN to the lysosome in mouse fibroblasts. This speaks to the broad importance of understanding how PGRN is trafficked to the lysosome in different cells types relevant to FTD. In fact, we have unpublished data suggesting that novel receptors contribute to lysosomal trafficking of PGRN in the brain. Importantly, all three groups have now identified cathepsin L as a putative cysteine cathepsin capable of cleaving progranulin in the lysosome, although other progranulin proteases likely exist. Further, the data from the Zhou/Hu paper support our hypothesis that granulins are not generated or found extracellularly at high levels under basal conditions, although more work is needed to confirm this in vivo. Finally, the Zhou/Hu paper reports that Grn+/- mice have reduced granulin levels comparable to the reduced PGRN levels (both decreased by ~50 percent), which corroborates our findings that granulins are haploinsufficient in FTD-GRN patient fibroblasts and brain tissue. Overall, all three of these papers shed light on the processing of intracellular PGRN into granulins in the lysosome and support the idea that granulins may regulate important functions needed to maintain proper lysosomal homeostasis.View all comments by Christopher Holler
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