Disorders with Synuclein Pathology and P arkinsonism

Abstract

A variety of neurodegenerative disorders are classified as synucleinopathies based on the presence of prominent α-synuclein pathology. These diseases include Parkinson disease (PD) and dementia with Lewy bodies (with neuronal Lewy body formation) and multiple system atrophy (with glial cytoplasmic inclusions). The normal function of α-synuclein includes regulation of pre-synaptic vesicles. Autosomal dominant PD can be due to coding mutations or multiplications of the α-synuclein gene (SNCA). The coding mutations are thought to lead to a gain of function, in particular acceleration of the formation of proto-fibrils. Duplications and triplications of SNCA lead to autosomal dominant PD with a gene dosage effect on age of onset and clinical severity; variants in the SNCA promoter which lead to an upregulation of SNCA expression are associated with an increased risk of sporadic PD. Key concepts αhyphen;Synuclein is deposited in the common neurodegenerative conditions Parkinson disease (PD), and dementia with Lewy bodies as neuronal cytoplasmic inclusions (Lewy bodies). The normal function of αhyphen;synuclein is incompletely understood but is likely to involve interaction with, and regulation of synaptic vesicles. There is some evidence that αhyphen;synuclein may have a role as a cellular chaperone and in interacting with the proteasome. Mendelian coding mutations in the αhyphen;synuclein gene (SNCA) can lead to autosomal dominant PD and dementia with Lewy bodies (DLB). SNCA mutations lead to an enhancement of protofibril formation as well as affecting normal αhyphen;synuclein function. SNCA duplications and triplications lead to autosomal dominant PD: an increase in the transcription of normal sequence SNCA can lead to disease. Promoter variation at the SNCA is associated with PD; in vitro evidence suggests that protective promoter alleles lead to a downregulation of SNCA expression. Keywords: α-synuclein; Parkinson disease; multiple system atrophy; Lewy body; dementia with Lewy bodies