Microglial lysosome dysfunction contributes to white matter pathology and TDP-43 proteinopathy in GRN-associated FTD

Cell Reports

卷:36

Ian R. Mackenzie¹  Leonard Petrucelli²  Chris W. Lee³  Mei Yue⁴  Mercedes Prudencio⁴  Shunsuke Koga⁴  Ariston L. Librero⁴  Yanwei Wu⁴  Monica Castanedes-Casey⁴  Wei Shao⁴  Tiffany W. Todd⁴  Yong-Jie Zhang⁴  Jimei Tong⁴  Dennis W. Dickson⁵ 

[1] Biomedical Research Institute of New Jersey, Cedar Knolls, NJ 07927, USA;

[2] Neurobiology of Disease Graduate Program, Mayo Graduate School, Mayo Clinic College of Medicine, Rochester, MN 55902, USA;

[3] Atlantic Health System, Morristown, NJ 07960, USA;

[4] Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA;

[5] Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC V6T 2B5, Canada;

关键词: progranulin;    PGRN;    granulin;    GRN;    FTD;    lysosome;   

DOI  :  

来源: DOAJ

【 摘 要 】

Summary: Loss-of-function mutations in the progranulin gene (GRN), which encodes progranulin (PGRN), are a major cause of frontotemporal dementia (FTD). GRN-associated FTD is characterized by TDP-43 inclusions and neuroinflammation, but how PGRN loss causes disease remains elusive. We show that Grn knockout (KO) mice have increased microgliosis in white matter and an accumulation of myelin debris in microglial lysosomes in the same regions. Accumulation of myelin debris is also observed in white matter of patients with GRN-associated FTD. In addition, our findings also suggest that PGRN insufficiency in microglia leads to impaired lysosomal-mediated clearance of myelin debris. Finally, Grn KO mice that are deficient in cathepsin D (Ctsd), a key lysosomal enzyme, have augmented myelin debris and increased neuronal TDP-43 pathology. Together, our data strongly imply that PGRN loss affects microglial activation and lysosomal function, resulting in the accumulation of myelin debris and contributing to TDP-43 pathology.

【 授权许可】

Unknown