Abstract

ObjectiveThe goal of this study was to investigate the effect of progranulin insufficiency on extracellular vesicles (EVs), a heterogeneous population of vesicles that may contribute to progression of neurodegenerative disease. Loss‐of‐function mutations in progranulin (GRN) are a major cause of frontotemporal dementia (FTD), and brains from GRN carriers with FTD (FTD‐GRN) exhibit signs of lysosomal dysfunction. Lysosomal dysfunction may induce compensatory increases in secretion of exosomes, EVs secreted from the endolysosomal system, so we hypothesized that progranulin insufficiency would increase EV levels in the brain.MethodsWe analyzed levels and protein contents of brain EVs from Grn–/– mice, which model the lysosomal abnormalities of FTD‐GRN patients. We then measured brain EVs in FTD‐GRN patients. To assess the relationship of EVs with symptomatic disease, we measured plasma EVs in presymptomatic and symptomatic GRN mutation carriers.Results Grn–/– mice had elevated brain EV levels and altered EV protein contents relative to wild‐type mice. These changes were age‐dependent, occurring only after the emergence of pathology in Grn–/– mice. FTD‐GRN patients (n = 13) had elevated brain EV levels relative to controls (n = 5). Symptomatic (n = 12), but not presymptomatic (n = 7), GRN carriers had elevated plasma EV levels relative to controls (n = 8).InterpretationThese data show that symptomatic FTD‐GRN patients have elevated levels of brain and plasma EVs, and that this effect is modeled in the brain of Grn–/– mice after the onset of pathology. This increase in EVs could influence FTD disease progression, and provides further support for EVs as potential FTD biomarkers.

Highlights

  • Loss-of-function mutations in the progranulin gene (GRN) are among the most common genetic causes of frontotemporal dementia (FTD), accounting for around 5% of all FTD cases and up to 25% of familial FTD cases.[1,2,3] Most of these mutations cause progranulin haploinsufficiency, primarily through nonsense-mediated decay.[1,2] Progranulin haploinsufficiency is, thought to drive FTD pathogenesis in GRN mutation carriers.Lysosomal dysfunction may be a mechanism by which progranulin haploinsufficiency causes FTD

  • Since the vesicles isolated from mouse brains likely include multiple extracellular vesicles (EVs) subtypes, we assessed vesicles of the size range of exosomes (50–150 nm) to determine if the increase in EVs might be associated with endolysosomal dysfunction

  • This study reports increased EV levels in the brain of Grn–/– mice and both frontal cortex and plasma of FTDGRN patients, indicating that increased EV secretion is a common effect of progranulin insufficiency

Read more

Summary

Introduction

Loss-of-function mutations in the progranulin gene (GRN) are among the most common genetic causes of frontotemporal dementia (FTD), accounting for around 5% of all FTD cases and up to 25% of familial FTD cases.[1,2,3] Most of these mutations cause progranulin haploinsufficiency, primarily through nonsense-mediated decay.[1,2] Progranulin haploinsufficiency is, thought to drive FTD pathogenesis in GRN mutation carriers.Lysosomal dysfunction may be a mechanism by which progranulin haploinsufficiency causes FTD. Loss-of-function mutations in the progranulin gene (GRN) are among the most common genetic causes of frontotemporal dementia (FTD), accounting for around 5% of all FTD cases and up to 25% of familial FTD cases.[1,2,3] Most of these mutations cause progranulin haploinsufficiency, primarily through nonsense-mediated decay.[1,2] Progranulin haploinsufficiency is, thought to drive FTD pathogenesis in GRN mutation carriers. Individuals homozygous for GRN mutations, resulting in nearly complete progranulin deficiency, develop the lysosomal storage disorder Neuronal Ceroid Lipofuscinosis (NCL).[4,5,6,7,8] Heterozygous GRN carriers typically have less than 50% of normal circulating progranulin levels,[9,10] and develop a 2020 The Authors.

Methods
Results
Conclusion
Full Text
Published version (Free)

Talk to us

Join us for a 30 min session where you can share your feedback and ask us any queries you have

Schedule a call