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Disorders with Synuclein Pathology and Parkinsonism

  1. Laura L Kilarski1,
  2. Vladimir L Buchman2,
  3. Huw R Morris1

Published Online: 15 MAR 2009

DOI: 10.1002/9780470015902.a0006031

eLS

eLS

How to Cite

Kilarski, L. L., Buchman, V. L. and Morris, H. R. 2009. Disorders with Synuclein Pathology and Parkinsonism. eLS. .

Author Information

  1. 1

    Cardiff University, School of Medicine, Cardiff, UK

  2. 2

    Cardiff University, School of Biosciences, Cardiff, UK

Publication History

  1. Published Online: 15 MAR 2009

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