Department of Genetics, Yale School of Medicine, New Haven, Connecticut, USA.
Interdepartmental Neuroscience Program, Yale University, New Haven, Connecticut, USA.
JCI Insight. 2021 Nov 22;6(22):e136147. doi: 10.1172/jci.insight.136147.
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.
颗粒体蛋白前体基因 (GRN) 中的遗传变异与多种神经退行性疾病相关，包括额颞叶痴呆、神经元蜡样脂褐质沉积症和阿尔茨海默病。这些遗传改变表现为 PGRN 表达减少导致的病理变化；因此，确定能够在体内调节 PGRN 水平的因素将增强我们对神经退行性变中 PGRN 的理解，并可能揭示新的潜在治疗靶点。在这里，我们报告通过减少小神经胶质细胞中的神经调节激酶 (Nlk) 来调节内吞作用/溶酶体途径，可以改变小鼠大脑中的总 Pgrn 水平。我们证明 Nlk 减少通过增强其通过内吞作用/溶酶体途径的运输来促进 Pgrn 降解，特别是在小神经胶质细胞中。此外，在小鼠中的遗传相互作用研究表明，Grn 杂合不足小鼠中的 Nlk 杂合性进一步降低了 Pgrn 水平，并诱导与 PGRN 缺乏相关的神经病理表型。我们的结果揭示了通过小神经胶质细胞的积极分解代谢来调节大脑中 Pgrn 水平的机制，并为 PGRN 相关疾病的病理生理学提供了见解。
