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

• Main Authors: James A. Duce, Bruce X. Wong, Hannah Durham, Jean-Christophe Devedjian, David P. Smith, David Devos
• Format: Article
• Language: English
• Published: BMC 2017-06-01
• Series: Molecular Neurodegeneration
• Subjects: α-synuclein; Iron; Dopamine; Endosomal trafficking; Oxidative stress; Post translational modification
• Online Access: http://link.springer.com/article/10.1186/s13024-017-0186-8

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.