Cholesterol dyshomeostasis compromises the physiological functions of glial cells in developing mouse cerebellum: insights from Niemann Pick type C mouse model

The Niemann Pick type C disease (NPCD) is a rare fatal metabolic disorder caused by mutations either on the NPC1 or NPC2 genes, which lead to the accumulation of endocytosed, unesterified cholesterol and other lipids within the late endosomal/lysosomal compartment. This decreases the metabolic active pool of unesterified cholesterol in the cytosol, affecting nearly all aspects of neuronal physiology (1). The principal neuropathological hallmark of NPCD is the degeneration and subsequent loss of Purkinje cells (PC), which is responsible for cerebellar dysfunction both in NPC patients and animal models. However, as in many other neurodegenerative pathologies, the neuronal loss is accompained by diffuse neuroinflammation, which has been described in several areas of the brain, and seems to play an important role in the pathogenesis of the disease. Indeed, several studies have shown that disease progression can be delayed with anti-inflammatory compounds (2). Although, a great interest has been focused on the symptomatic stages of pathology, the possibility that early neural development processes are impaired by NPC1-deficiency has mostly been neglected, since patients do not apparently show early developmental defects and neuropathological signs appear in Npc1−/− mice in the juvenile/young adult age. However, we disclosed the presence of significant defects in cerebellar morphogenesis of NPC1 mice, such as a decreased number of granule neurons, severe cerebellar dysmyelination and a derangement of synaptic connectivity on PC during the second post-natal week of age (3,4,5). In light of their important role in developmental processes, including neuro-/gliogenesis, axonal outgrowth, synaptic patterning and elimination of apoptotic and debris cells, we hypothesize that dysfunction of microglia and/or astrocytes could contribute to the pathogenesis of NPCD. Supporting this hypothesis, we have achieved preliminary evidence of molecular and morphological dysregulations of these cells in the cerebellum of Npc1-deficient mice compared to controls at early developmental stages. This issue is investigated by using specific markers of glial cells and neuroinflammation, such as Iba1, GFAP, CD68, CD11b, and focusing our attention to the interaction between neurons and glial cells in post-natal (PN) developing cerebellum (PN8-30). References: 1. Vanier et al., 2015; J Inherit Metab Dis. 38:187-99. 2. Bosch and Kielian, 2015; Front Neurosci. 9:417. 3. Canterini et al., 2017; Hum Mol Genet. 0:1-13. 4. Caporali et al., 2016; Acta Neuropathol. Commun. 1:4-94. 5. Nusca et al., 2014; Neurobiol. of Dis. 70:117-126.