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 ε4 homozygosity, deposition of Aβ occurs mimicking Alzheimer disease (AD). Since AD is frequently associated with neuronal expression of α-synuclein, we investigated phosphorylated α-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 ε4 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 α-synuclein frequently colocalized. This study first documents α-synucleinopathy in NPC1. This observation suggests that the defect in intracellular cholesterol trafficking in NPC1 may provoke aberrant phosphorylation of α-synuclein and tau, and that this phosphorylation is enhanced by the ApoE ε4 allele. Thus, elucidation of metabolic pathways in NPC1 could provide clues to common mechanisms associated with neurodegeneration.