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

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.

Minimotifs dysfunction is pervasive in neurodegenerative disorders

“…Furthermore, there are at least a dozen other PTMs that modulate tau aggregation [72,215]. Lewy bodies are ubiquitylated, sumoylated, phosphorylated, nitrosylated, and also have a unique PTM created by a dopamine radical adduct [150,216,217].…”

Aggregation and conformation of alpha-synuclein: effects of ligand binding and phosphomimetics

“…It has been well documented that αsyn found within the LBs of PD patients has undergone a variety of post-translational modifications (PTMs), which include phosphorylation of serine and tyrosine residues, acetylation of the N-terminus and ubiquitination of lysine residues (Barrett and Greenamyre, 2015;Duce et al, 2017;Oueslati., 2016;Fujiwara et al, 2002;Popova et al, 2015;Schmid et al, 2013). The majority of PTM sites are also known to be located within the highly disordered C-terminal region of the protein.…”

“…Non-physiological solvent conditions such as low pH or the presence of alcohols can significantly alter the CSD of a protein (Beveridge et al, 2015;Duce et al, 2017) so care must be taken to keep solution conditions as physiologically relevant as possible.…”

“…Transition metals, which include copper, iron, zinc, magnesium and manganese, are essential co-factors for almost half of all proteins (Waldron et al, 2009). For example, tyrosine hydroxylase, which catalyses the conversion of tyrosine to dopamine, requires ferrous iron to complete its function (Fitzpatrick, 1989;Duce et al, 2017). Correct brain development in infancy is also known to require optimum iron levels (Lozoff and Georgieff, 2006), and physiological iron is also important for the regulation of cellular development, mitochondrial respiration, and the production of myelin (Duce et al, 2017).…”

“…For example, tyrosine hydroxylase, which catalyses the conversion of tyrosine to dopamine, requires ferrous iron to complete its function (Fitzpatrick, 1989;Duce et al, 2017). Correct brain development in infancy is also known to require optimum iron levels (Lozoff and Georgieff, 2006), and physiological iron is also important for the regulation of cellular development, mitochondrial respiration, and the production of myelin (Duce et al, 2017). Iron response elements are also a known factor in post-transcriptional control of gene expression, and these are commonly found in proteins involved in iron homeostasis (Wang and Pantopoulos, 2011).…”