Abstract

A variety of neurodegenerative disorders are classified as synucleinopathies based on the presence of prominent -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 -synuclein includes regulation of pre-synaptic vesicles. Autosomal dominant PD can be due to coding mutations or multiplications of the -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

• hyphen;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 hyphen;synuclein is incompletely understood but is likely to involve interaction with, and regulation of synaptic vesicles.
  
• There is some evidence that hyphen;synuclein may have a role as a cellular chaperone and in interacting with the proteasome.
  
• Mendelian coding mutations in the hyphen;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 hyphen;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.