RRC ID 78262
Author Takahashi H, Bhagwagar S, Nies SH, Ye H, Han X, Chiasseu MT, Wang G, Mackenzie IR, Strittmatter SM.
Title Reduced progranulin increases tau and α-synuclein inclusions and alters mouse tauopathy phenotypes via glucocerebrosidase.
Journal Nat Commun
Abstract Comorbid proteinopathies are observed in many neurodegenerative disorders including Alzheimer's disease (AD), increase with age, and influence clinical outcomes, yet the mechanisms remain ill-defined. Here, we show that reduction of progranulin (PGRN), a lysosomal protein associated with TDP-43 proteinopathy, also increases tau inclusions, causes concomitant accumulation of α-synuclein and worsens mortality and disinhibited behaviors in tauopathy mice. The increased inclusions paradoxically protect against spatial memory deficit and hippocampal neurodegeneration. PGRN reduction in male tauopathy attenuates activity of β-glucocerebrosidase (GCase), a protein previously associated with synucleinopathy, while increasing glucosylceramide (GlcCer)-positive tau inclusions. In neuronal culture, GCase inhibition enhances tau aggregation induced by AD-tau. Furthermore, purified GlcCer directly promotes tau aggregation in vitro. Neurofibrillary tangles in human tauopathies are also GlcCer-immunoreactive. Thus, in addition to TDP-43, PGRN regulates tau- and synucleinopathies via GCase and GlcCer. A lysosomal PGRN-GCase pathway may be a common therapeutic target for age-related comorbid proteinopathies.
Volume 15(1)
Pages 1434
Published 2024-2-16
DOI 10.1038/s41467-024-45692-3
PII 10.1038/s41467-024-45692-3
PMID 38365772
PMC PMC10873339
MeSH Alzheimer Disease* / metabolism Animals Glucosylceramidase / genetics Glucosylceramidase / metabolism Humans Male Mice Progranulins Proteostasis Deficiencies* Tauopathies* alpha-Synuclein / genetics alpha-Synuclein / metabolism tau Proteins / genetics tau Proteins / metabolism
Mice RBRC02370