Molecular Neurodegeneration (Jun 2017)

Post translational changes to α-synuclein control iron and dopamine trafficking; a concept for neuron vulnerability in Parkinson’s disease

  • James A. Duce,
  • Bruce X. Wong,
  • Hannah Durham,
  • Jean-Christophe Devedjian,
  • David P. Smith,
  • David Devos

DOI
https://doi.org/10.1186/s13024-017-0186-8
Journal volume & issue
Vol. 12, no. 1
pp. 1 – 12

Abstract

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Abstract Parkinson’s disease is a multifactorial neurodegenerative disorder, the aetiology of which remains elusive. The primary clinical feature of progressively impaired motor control is caused by a loss of midbrain substantia nigra dopamine neurons that have a high α-synuclein (α-syn) and iron content. α-Syn is a neuronal protein that is highly modified post-translationally and central to the Lewy body neuropathology of the disease. This review provides an overview of findings on the role post translational modifications to α-syn have in membrane binding and intracellular vesicle trafficking. Furthermore, we propose a concept in which acetylation and phosphorylation of α-syn modulate endocytic import of iron and vesicle transport of dopamine during normal physiology. Disregulated phosphorylation and oxidation of α-syn mediate iron and dopamine dependent oxidative stress through impaired cellular location and increase propensity for α-syn aggregation. The proposition highlights a connection between α-syn, iron and dopamine, three pathological components associated with disease progression in sporadic Parkinson’s disease.

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