Impaired Autophagy in the Lipid-Storage Disorder Niemann-Pick Type C1 Disease

Abstract

SUMMARY Autophagy dysfunction has been implicated in misfolded protein accumulation and cellular toxicity in several diseases. Whether alterations in autophagy also contribute to the pathology of lipid storage disorders is not clear. Here we show defective autophagy in Niemann-Pick type C1 (NPC1) disease associated with cholesterol accumulation, where maturation of autophagosomes is impaired due to defective amphisome formation caused by failure in SNARE machinery, whilst the lysosomal proteolytic function remains unaffected. Expression of functional NPC1 protein rescues this defect. Inhibition of autophagy also causes cholesterol accumulation. Compromised autophagy was seen in disease-affected organs of Npc1 mutant mice. Of potential therapeutic relevance is that HP-β-cyclodextrin, which is used for cholesterol depletion treatment, impedes autophagy, whereas stimulating autophagy restores its function independent of amphisome formation. Our data suggest that a low dose of HP-β-cyclodextrin that does not perturb autophagy, coupled with an autophagy inducer, may provide a rational treatment strategy for NPC1 disease.

High sphingomyelin levels induce lysosomal damage and autophagy dysfunction in Niemann Pick disease type A

“…It has been proposed that altered lipid content (i.e., high cholesterol or ganglioside levels) may contribute to autophagy impairment. [20][21][22][23][24] On the other hand, the lipid that most significantly accumulates in neurons from ASMko mice is SM. 10 Hence, we directly tested whether SM accumulation was responsible for the autophagosome-lysosome alterations observed in the ASMko mice brain.…”

“…Moreover, ASMko mice brains show cholesterol deposits 29,30 and the accumulation of this lipid impairs lysosomal function in different LSDs. 21,22,24 To test cholesterol involvement, NPA fibroblasts were incubated with methyl-b-cyclodextrin, which sequesters this lipid without affecting SM. 31 Treatment for 24 h with 0.3 mM methyl-b-cyclodextrin had no effect on LC3-II levels ( Figure 5c) despite its efficiency in reducing cholesterol levels by 16% (Figure 5d), similar to the 15% SM reduction promoted by FB1.…”

“…21 Studies in Niemann Pick type C patient cells and in mouse models showed that cholesterol also influences autophagy initiation by enhancing Beclin1 levels 40 or SNARE-mediated autophagosome maturation. 24 Increased ganglioside levels promote autophagy initiation and do not affect autophagosome-lysosome fusion but impair efficient clearance in different sphingolipidosis. 23 We here identify SM as a relevant lipid in autophagy regulation.…”

Small-molecule enhancers of autophagy modulate cellular disease phenotypes suggested by human genetics

“…We have recently shown that small-molecule enhancers of autophagy, such as CBZ, can rescue impairment of autophagic flux observed in NPC1, a lipid/lysosomal storage disease exhibiting accumulation of cholesterol in the late endosomal/lysosomal compartments and associated with degeneration of the cerebellum and liver in patients (17,18). These enhancers also suppress cell death in NPC1 patient-specific hiPSC-derived neuronal and hepatic cells, which normally display cholesterol accumulation, impaired autophagic flux, and increased cell death in the absence of any external stressors relative to control cells (18).…”

“…In the context of protein aggregation disorders, carbamazepine (CBZ)-induced autophagy reduces accumulation of α1-antitrypsin in liver cells and rescues hepatic fibrosis in mice (15), whereas rapamycin-or trehaloseinduced autophagy clears α-synuclein and mutant huntingtin aggregates in neurodegenerative disease models, among others (16). Autophagy defects linked to the lysosomal storage disorder Niemann-Pick type C1 disease (NPC1; caused by mutation in the NPC1 protein) can be restored by stimulating autophagy with rapamycin or CBZ, which is cytoprotective in NPC1 diseaserelevant cells (17,18). In the context of CD, small molecules have been shown to promote favorable immune phenotypes.…”