Disorders with Synuclein Pathology and Parkinsonism

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

Figure 1.

Structure of α‐synuclein showing the location of the Mendelian coding mutations. Kindly provided by Dr Morris.

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Kilarski, Laura L, Buchman, Vladimir L, and Morris, Huw R(Mar 2009) Disorders with Synuclein Pathology and Parkinsonism. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0006031]