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

Area of Science:

• Neuroscience
• Genetics
• Cell Biology

Background:

• Loss-of-function mutations in the progranulin gene (GRN) are a primary genetic cause of frontotemporal dementia (FTD).
• GRN-associated FTD presents with TDP-43 inclusions and neuroinflammation, but the underlying disease mechanisms are not fully understood.

Purpose of the Study:

• To investigate the role of progranulin (PGRN) in microglial function and its contribution to the pathogenesis of GRN-associated frontotemporal dementia (FTD).
• To elucidate the cellular and molecular mechanisms by which PGRN deficiency leads to neurodegeneration.

Main Methods:

• Utilized Grn knockout (KO) mouse models to study microglial activation and lysosomal function in white matter.
• Examined white matter tissue from Grn KO mice and patients with GRN-associated FTD for myelin debris accumulation.
• Investigated the impact of PGRN deficiency on lysosomal-mediated clearance pathways, including the role of cathepsin D (Ctsd).

Main Results:

• Grn KO mice exhibited increased microgliosis and accumulation of myelin debris within microglial lysosomes, mirroring findings in human FTD patients.
• PGRN insufficiency in microglia impaired the clearance of myelin debris via lysosomal pathways.
• Grn KO mice lacking cathepsin D showed exacerbated myelin debris accumulation and increased TDP-43 pathology.

Conclusions:

• Progranulin (PGRN) loss disrupts microglial activation and lysosomal clearance of myelin debris.
• Accumulation of myelin debris due to PGRN deficiency contributes to TDP-43 pathology in the context of frontotemporal dementia (FTD).
• These findings highlight a critical role for PGRN in maintaining microglial homeostasis and preventing neurodegenerative processes.