NPC1 deficiency impairs cerebellar postnatal development of microglia and climbing fiber refinement in a mouse model of Niemann-Pick Type C disease

Abstract

Little is known about the effects of NPC1 deficiency in brain development and whether these effects contribute to neurodegeneration in Niemann-Pick disease type C (NPC). Degeneration of cerebellar Purkinje cells occurs at an earlier stage and to a greater extent in NPC; therefore, we analyzed the effect of NPC1 deficiency on microglia and on climbing fiber synaptic refinement during cerebellar postnatal development using the Npc1 nmf164 mouse. Our analysis revealed that NPC1 deficiency leads to early phenotypic changes in microglia that are not associated with an innate immune response. However, the lack of NPC1 in Npc1 nmf164 mice significantly affected the early development of microglia by delaying the radial migration, increasing the proliferation and impairing the differentiation of microglia precursor cells during postnatal development. Additionally, increased phagocytic activity of differentiating microglia was observed at the end of the second postnatal week in Npc1 nmf164 mice. Moreover, significant climbing fiber synaptic refinement deficits along with an increased engulfment of climbing fiber synaptic elements by microglia were found in Npc1 nmf164 mice, suggesting that profound developmental defects in microglia and synaptic connectivity might precede and predispose Purkinje cells to early neurodegeneration in NPC.

The appearance of phagocytic microglia in the postnatal brain of Niemann Pick type C mice is developmentally regulated and underscores shortfalls in fine odor discrimination

“…The increased microglia phagocytic activity at P15 appears more likely related to synaptic changes and maturation of climbing and mossy fibers, which typically maximizes between P12 and P17 (Hashimoto & Kano, 2005). Indeed, the presence of an exaggerated CF-PCs synapse elimination in Npc1-defcient mice has been reported recently (Boyle et al, 2020;Colombo et al, 2021).…”

“…Dysfunctional lipid export from lysosomes disrupts intracellular lipid homeostasis, altering developmental trajectories and predisposing to the appearance of overt pathological signs in Npc1-deficient mouse models, including a progressive and stereotyped Purkinje cell loss and microgliosis (Baudry et al, 2003;Fiorenza et al, 2022;Martin et al, 2019;Pressey et al, 2012). However, while pro-inflammatory microglia activation, at symptomatic stages typically occurs both in patients and preclinical models (Cologna et al, 2014;Colombo et al, 2021;Cougnoux et al, 2018;Pressey et al, 2012), how microglia cells respond to altered neurodevelopmental dynamics remains not completely understood (Boyle et al, 2020;Colombo et al, 2021).…”

Phenotypic expression of swallowing function in Niemann–Pick disease type C1

“…We acknowledge that our interpretive rating scales may not be widely accessible or recognized by other health care providers. However, these tools offer a summative interpretive analysis guiding clinical management and treatment outcome, unlike other methodologies in NPC1 literature [ 5 , 18 ]. Our report further expands upon the NPC1 phenotype to include swallowing safety, need for diet modifications, laryngeal penetration, aspiration risks, and other speech domains, which have not been addressed comprehensively in the literature.…”

Gender-Specific Effects of Two Treatment Strategies in a Mouse Model of Niemann-Pick Disease Type C1

“…These findings correlate with other data on the reduction of brain weight in NPC disease [ 61 , 71 , 107 ]. Significant volume reductions in the cerebellar hemispheres, the medulla oblongata, the corpus callosum, and the olfactory bulb of NPC1 −/− mice have been described [ 68 , 108 , 109 , 110 ], which could contribute to the difference in brain weight [ 24 , 109 ]. A further example at the terminal stages in the murine NPC1 model is an age-dependent Purkinje cell loss of 96% [ 22 , 34 , 107 , 109 ].…”