Reduced progranulin increases tau and α-synuclein inclusions and alters mouse tauopathy phenotypes via glucocerebrosidase

Hideyuki Takahashi, Sanaea Bhagwagar, Sarah H. Nies, Hongping Ye, Xianlin Han, Marius T. Chiasseu, Guilin Wang, Ian R. Mackenzie and Stephen M. Strittmatter ()
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Hideyuki Takahashi: Yale University School of Medicine
Sanaea Bhagwagar: Yale University School of Medicine
Sarah H. Nies: Yale University School of Medicine
Hongping Ye: University of Texas Health Science Center At San Antonio
Xianlin Han: University of Texas Health Science Center At San Antonio
Marius T. Chiasseu: Yale University School of Medicine
Guilin Wang: Yale University
Ian R. Mackenzie: University of British Columbia and Vancouver General Hospital
Stephen M. Strittmatter: Yale University School of Medicine

Nature Communications, 2024, vol. 15, issue 1, 1-23

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-45692-3

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