Aberrant Phosphorylation of α-Synuclein in Human Niemann-Pick Type C1 Disease

Abstract

Niemann-Pick type C1 disease (NPC1) is an autosomal recessive neurovisceral storage disease caused by the mutation of NPC1 gene, resulting in perturbed intracellular transport of unesterified cholesterol. In NPC1, early-onset tauopathy is a constant feature. In addition, in NPC1 patients with ApoE epsilon4 homozygosity, deposition of A beta occurs mimicking Alzheimer disease (AD). Since AD is frequently associated with neuronal expression of alpha-synuclein, we investigated phosphorylated alpha-synuclein (psyn) immunoreactivity in the brains of 12 NPC1 patients, ages at death ranging from 9 months to 55 years. Psyn immunoreactivity was demonstrated in the perikarya of storage neurons and oligodendroglia in 10 cases. The immunoreactivity appeared more intense in subjects who had the ApoE epsilon4 allele. Lewy bodies were found in the substantia nigra in 2 of these cases. The psyn immunoreactivity was most intense in the substantia nigra where tauopathy was most severe. Phosphorylated tau and alpha-synuclein frequently colocalized. This study first documents alpha-synucleinopathy in NPC1. This observation suggests that the defect in intracellular cholesterol trafficking in NPC1 may provoke aberrant phosphorylation of alpha-synuclein and tau, and that this phosphorylation is enhanced by the ApoE epsilon4 allele. Thus, elucidation of metabolic pathways in NPC1 could provide clues to common mechanisms associated with neurodegeneration.

Bidirectional links between Alzheimer's disease and Niemann–Pick type C disease

“…This finding suggests that ApoE4 may be the cause of aberrant Aβ deposition as well as accelerated tauopathy in NPC. The same authors observed α-synucleinopathy and Lewy bodies in the majority of NPC1 cases (Saito et al, 2004). Lewy bodies are a pathological hallmark of Parkinson disease and dementia with Lewy bodies, and the major protein constituent is phosphorylated α-synuclein.…”

Genetic perspective on the role of the autophagy-lysosome pathway in Parkinson disease

“…Some pathological evidence from autopsies of Niemann-Pick type C patients' brains, suggest that SNCA may be aberrantly phosphorylated and aggregate in Lewy bodies. 92,93 Although none of these genes was implicated in human genetic studies, it is possible that rare mutations in these genes can be found in PD; therefore, sequencing of GLA and NPC1 in different PD cohorts is important for determining if they have a role in PD.…”

Disruption of Protein Quality Control in Parkinson's Disease

“…Gaucher's and Niemann-Pick Disease, as Well as ATPase Gene Mutations, Increase Parkinsonism Risk Interestingly, an increased susceptibility to develop parkinsonism and abnormal a-synuclein inclusion formation has been observed in patients with lysosomal storage disorders, including Gaucher's disease and Niemann-Pick disease (Tayebi et al 2001;Varkonyi et al 2003;Saito et al 2004). In addition, mutations in a lysosomal protein encoded by the gene ATP13A2, which is believed to promote UPS and lysosomal dysfunction, are associated with a juvenile onset parkinsonian disorder known as KuforRakeb syndrome (KRS) (Ramirez et al 2006).…”