Year: 2021
Type: article
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.
Source: JCI Insight
Authors: Tingting Dong, Leon Tejwani, Youngseob Jung, Hiroshi Kokubu, Kimberly Luttik, Terri M. Driessen, Janghoo Lim
Institution: Yale University
Language: English
Subfield: Neurology
Field: Neuroscience
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $4,100
Funders: Yale University, Denali Therapeutics, Shanghai Jiao Tong University, Raymond and Beverly Sackler Institute for Biological, Physical and Engineering Sciences, Yale University, School of Medicine, Shanghai Jiao Tong University, National Institute on Aging, National Institute of Mental Health, National Institute of Neurological Disorders and Stroke
Awards: Investigating the Pathogenesis of Cerebellar Neurodegeneration, The role of TRIO signaling in neuronal development, synaptic function, and circuit connectivity, Cellular and Molecular Studies of SBMA Neuromuscular Disease, Microglial regulation of Progranulin levels, Regulation of inhibitory interneuron development, Neurobiology of Cortical Systems, Evaluation of a novel NLK function in lysosome biogenesis and neurodegenerative diseases
OpenAlex ID: W3203993850