Microglia regulate brain progranulin levels through the endocytosis/lysosomal pathway

Abstract

Genetic variants in Granulin ( GRN ), which encodes the secreted glycoprotein progranulin (PGRN), are associated with several neurodegenerative diseases, including frontotemporal lobar degeneration, neuronal ceroid lipofuscinosis, and Alzheimer’s disease. These genetic alterations manifest in pathological changes due to a reduction of PGRN expression; therefore, identifying factors that can modulate PGRN levels in vivo would enhance our understanding of PGRN in neurodegeneration and could reveal novel potential therapeutic targets. Here, we report that modulation of the endocytosis/lysosomal pathway via reduction of Nemo-like kinase (Nlk) in microglia, but not in neurons, can alter total brain Pgrn levels in mice. We demonstrate that Nlk reduction promotes Pgrn degradation by enhancing its trafficking through the endocytosis/lysosomal pathway, specifically in microglia. Furthermore, genetic interaction studies in mice showed that Nlk heterozygosity in Grn haploinsufficient mice further reduces Pgrn levels and induces neuropathological phenotypes associated with PGRN deficiency. Our results reveal a mechanism for Pgrn level regulation in the brain through the active catabolism by microglia and provide insights into the pathophysiology of PGRN-associated diseases.

Progranulin Insufficiency Affects Lysosomal Homeostasis in Retinal Pigment Epithelium

“…Grn and Tmem106b double knockout mice showed a significant increase of lysosomal proteins in neuron and microglia as compared to wildtype and Grn single knockout mice (39). Nemo-like kinase regulated the expression level of progranulin via lysosomal degradation in microglia, but not through neurons (40). These modifiers might affect the level of lysosome biogenesis in progranulin deficient RPE cells.…”

Progranulin released from microglial lysosomes reduces neuronal ferroptosis after cerebral ischemia in mice

“…35 Our findings are consistent with other studies that neurons and microglia are major contributors to PGRN in the brain. 35–37…”

“…35 Our findings are consistent with other studies that neurons and microglia are major contributors to PGRN in the brain. [35][36][37] Ferroptosis is an important cell death pathway in acute brain injury, including cerebral ischemia and hemorrhage, 38 initiated by GSH depletion or GPX4 activity inhibition, 39,40 with GSH essential for GPX4 activity. GPX4 expression decreases during the acute phase of stroke, and increasing GPX4 expression can rescue neurons from ferroptosis and improve neurofunctional outcomes after stroke.…”

Preclinical Interventions in Mouse Models of Frontotemporal Dementia Due to Progranulin Mutations

“…In the brain under normal conditions, neuronal progranulin accounts for the majority of progranulin, as conditional deletion of a floxed progranulin allele using nestin-Cre leads to a > 50% reduction in progranulin, and using CaMKII-Cre leads to comparable reductions in brain regions where it is expressed [95,96]. Microglia are another source of progranulin in the brain, and activated microglia upregulate progranulin expression [97]. Despite these two cell types producing significant amounts of progranulin, conditional deletion of either neuronal or microglial progranulin is insufficient to recapitulate the gliosis and lysosomal dysfunction that are seen in Grn -/mice [95,96,98].…”