Endo‐Lysosomal Dysfunction and Neuronal‐Glial Crosstalk in Niemann Pick Type C Disease

Abstract

AbstractMicroglial activation is a neuropathological hallmark of the lysosomal storage disease Niemann‐Pick type C (NPC). Whole‐body knockout of NPC1 results in enhanced phagocytic uptake and impaired myelin turnover in microglia that precede neuronal death. Npc1‐ deficient microglia are characterized by accumulation of multivesicular bodies and impaired endo‐lysosomal trafficking of lipids while lysosomal degradation remains preserved. To study a cell‐autonomous function of NPC1 in microglia, we generated a conditional knock‐out of NPC1 in myeloid cells by crossing Npc1 flox/flox mice with Cx3cr1 +/Cre mice and characterized microglial, astrocytic and neuronal phenotypes at different pathological stages using mass spectrometry, immunohistochemistry and PET imaging. Microglial activation was the first pathological alteration detected in the brain upon loss of NPC1 in myeloid cells, reflected by altered lipidomic profiles and disease‐associated microglial signatures. Microgliosis was followed by astrogliosis as visualized by immunohistochemistry and TSPO‐ PET and Deprenyl‐D2‐PET imaging, respectively. Furthermore, the loss of microglial NPC1 resulted in neuronal injuries (axonal spheroids) and motor deficits that were detected at the age of 7 months.Our work reveals that a specific loss of NPC1 in myeloid cells is sufficient to trigger pathology in other brain cells, suggesting that a pathological cascade initiated by microglial dysfunction may propagate to astrocytes and neurons.