Reduction of Nemo-like kinase increases lysosome biogenesis and ameliorates TDP-43-related neurodegeneration

Tejwani, Leon; Kokubu, Hiroshi; Lee, Paul J.; Xiang, Yangfei; Luttik, Kimberly; Soriano, Armand; Yoon, Jennifer R.; Park, Junhyun; Ro, Hannah; Ju, Hyoungseok; Liao, Clara; Tieze, Sofia Massaro; Rigo, Frank; Jafar‐Nejad, Paymaan; Lim, Janghoo

doi:10.1101/2020.04.19.049395

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“…We have recently identified Nlk as a negative regulator of the lysosome in neurons ( 46 ). Therefore, because Pgrn is trafficked to and degraded by the lysosome ( 35 , 36 , 47 ), we wondered whether partial loss of Nlk alters the levels of Pgrn.…”

Section: Resultsmentioning

confidence: 99%

Microglia regulate brain progranulin levels through the endocytosis/lysosomal pathway

et al. 2021

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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.

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