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

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 alpha-synuclein (alpha-syn) and iron content. alpha-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 alpha-syn have in membrane binding and intracellular vesicle trafficking. Furthermore, we propose a concept in which acetylation and phosphorylation of alpha-syn modulate endocytic import of iron and vesicle transport of dopamine during normal physiology. Disregulated phosphorylation and oxidation of alpha-syn mediate iron and dopamine dependent oxidative stress through impaired cellular location and increase propensity for alpha-syn aggregation. The proposition highlights a connection between alpha-syn, iron and dopamine, three pathological components associated with disease progression in sporadic Parkinson's disease.