Niemann–Pick type C disease: cellular pathology and pharmacotherapy

Abstract

Niemann–Pick type C disease (NPCD) was first described in 1914 and affects approximately 1 in 150 000 live births. It is characterized clinically by diverse symptoms affecting liver, spleen, motor control, and brain; premature death invariably results. Its molecular origins were traced, as late as 1997, to a protein of late endosomes and lysosomes which was named NPC1. Mutation or absence of this protein leads to accumulation of cholesterol in these organelles. In this review, we focus on the intracellular events that drive the pathology of this disease. We first introduce endocytosis, a much‐studied area of dysfunction in NPCD cells, and survey the various ways in which this process malfunctions. We briefly consider autophagy before attempting to map the more complex pathways by which lysosomal cholesterol storage leads to protein misregulation, mitochondrial dysfunction, and cell death. We then briefly introduce the metabolic pathways of sphingolipids (as these emerge as key species for treatment) and critically examine the various treatment approaches that have been attempted to date.

Shedding Light on the Dark Side of the Microglia

“…Indeed, Kavetsky et al (2019) investigated NPC nmf164 mice given for 5 weeks either a Western diet or a regular diet. Niemann-Pick type C is a genetic condition with mutations in the NPC genes (Npc1/2), which most notably lead to dysfunctional lysosomes (Wheeler and Sillence, 2019). While looking at microglia in the molecular layer of the cerebellum of both males and females with transmission electron microscopy, the authors identified DM processes interacting with synapses, a phenomenon especially seen in the mice given a Western diet (Kavetsky et al, 2019).…”

An Erg11 lanosterol 14-α-demethylase-Arv1 complex is required for Candida albicans virulence

“…Ceramide synthesis occurs in the ER, the organelle whose morphology is distorted in Scarv1 cells [44]. Ceramide hyper-accumulation and its mislocalization is seen in Niemann-Pick type C [45], Gaucher disease [46], and cystic fibrosis [47] patients, and is a contributor to the progression of these diseases. It remains to be examined if and how ceramide accumulation affects sterol metabolism.…”

Glial contribution to cyclodextrin-mediated reversal of cholesterol accumulation in murine NPC1-deficient neuronsin vivo

“…Niemann-Pick type C (NPC) disease (OMIM #257220, OMIM #607625) is a rare, autosomal recessive and ultimately fatal lysosomal storage disorder with variable disease onset, multiple visceral and neurologic symptoms and diverging life spans (Bräuer et al, 2019;Gowrishankar et al, 2020;Hammond et al, 2019;Vanier, 2010;Wheeler and Sillence, 2020). The disease is caused by mutations in NPC1 (Loftus et al, 1997) or NPC2 (Naureckiene et al, 2000) that encode a membrane-resident and an intralumenal component of the endosomal-lysosomal .…”