Microglial waste recycling problems linked to white matter damage and TDP-43 protein buildup in GRN-related frontotemporal dementia

Loss-of-function mutations in the progranulin gene are a major cause of frontotemporal dementia.

• Grn knockout mice exhibit increased activation of microglia in white matter and an accumulation of myelin debris within microglial lysosomes.
• Myelin debris accumulation is also present in the white matter of patients with GRN-associated frontotemporal dementia.
• PGRN insufficiency in microglia may impair the clearance of myelin debris through lysosomal mechanisms.
• Grn knockout mice lacking cathepsin D show heightened myelin debris and increased neuronal TDP-43 pathology.
• Data suggest that PGRN loss impacts microglial activation and lysosomal function, contributing to TDP-43-related disease processes.

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