Neurodegeneration in Heterozygous Niemann-Pick Type C1 (NPC1) Mouse

Abstract

Niemann-Pick type C1 (NPC1) disease is an autosomal recessive, fatal disorder characterized by a defect in cholesterol trafficking and progressive neurodegeneration. The disease is predominantly caused by mutations in the NPC1 gene; however, it has been assumed that heterozygous NPC1 mutations do not cause any symptoms. Here we demonstrate that cholesterol accumulation does not occur in young mouse brains; however, it does in aged (104 -106-week-old) NPC1؉/؊ mouse brains. In addition, Purkinje cell loss was observed in aged NPC1؉/؊ mouse cerebellums. Immunoblot analysis using anti-phospho-tau antibodies (AT-8, AT-100, AT-180, AT-270, PHF-1, and SMI-31) demonstrates the site-specific phosphorylation of tau at Ser-199, Ser-202, Ser-212, and Thr-214 in the brains of aged NPC1؉/؊ mice. Mitogen-activated protein kinase, a potential serine kinase known to phosphorylate tau, was activated, whereas other serine kinases, including glycogen synthase kinase 3␤, cyclin-dependent kinase 5, or stress-activated protein kinase/c-Jun N-terminal kinase were not activated. Cholesterol level in the lipid raft isolated from the cerebral cortices, ATP level, and ATP synthase activity in the cerebral cortices significantly decreased in the aged NPC1؉/؊ brains compared with those in the NPC1؉/؉ brains. All of these changes observed in NPC1؉/؊ brains were determined to be associated with aging and were not observed in the age-matched NPC1؉/؉ brains. These results clearly demonstrate that heterozygous NPC1 impairs neuronal functions and causes neurodegeneration in aged mouse brains, suggesting that human heterozygous NPC1 mutations may be a risk factor for neurodegenerative disorders, such as tauopathy, in the aged population.

Cholesterol Oxidation Products Are Sensitive and Specific Blood-Based Biomarkers for Niemann-Pick C1 Disease

“…On the other hand, Purkinje cell loss and enhanced phosphorylation of tau is present in aged Npc1 +/− mice, and in a feline NPC1 model heterozygotic cats exhibit intermediate biochemical phenotypes for cholesterol esterification and liver lipid accumulation (43,44). Moreover, abnormal filipin staining patterns have been reported in skin fibroblasts from obligate human heterozygotes, indicating accumulation of lysosomal free cholesterol, which may serve as substrate for non-enzymatic formation of cholesterol oxidation products (45).…”

Niemann-Pick C Disease Gene Mutations and Age-Related Neurodegenerative Disorders

“…In two of six PD patients (33%) heterozygous for disease-associated NPC1/2 variants impaired vertical gaze was found on clinical examination, an atypical sign for PD and the key feature of NPC, and one of these patients developed concomitant psychiatric symptoms early in the disease course. Findings from animal models highlight that heterozygous NPC1 mutations affect neuronal function and neurodegenerative disease status, particularly in the context of aging [44], [45]. Further, several studies suggest the possibility of symptomatic heterozygotes in human NPC: Josephs et al proposed one mutant NPC1 allele as the cause of parkinsonian tremor in a 75-year-old patient [46].…”

Variation in NPC1, the gene encoding Niemann–Pick C1, a protein involved in intracellular cholesterol transport, is associated with Alzheimer disease and/or aging in the Polish population

“…While the npc-1 , npc-2 deficiency functions in a steroid hormonal pathway [21] and Npc1 deficiency does not appear to limit somatic steroid synthesis in mice [49], the link between the Dauer-formation pathway and longevity involves insulin-signaling and general metabolism [4, 18, 29] which NPC1 possibly influences through its effects on liver metabolism [8]. A goal of future work will be to determine if rs18050810, T allele; rs1631685, T allele; and/or rs1788799, G allele are associated with decreased or increased NPC1 function, it is likely that it will be the former since aged NPC1 heterozygous mice (NPC1 ±) show neurodegeneration [50]. …”