Metal-triggered structural transformations, aggregation, and fibrillation of human alpha-synuclein. A possible molecular NK between Parkinson's disease and heavy metal exposure.

By Vladimir N Uversky, Jie Li, A. Fink. Journal of Biological Chemistry, 2001

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Parkinson's disease involves the aggregation of alpha-synuclein to form fibrils, which are the major constituent of intracellular protein inclusions (Lewy bodies and Lewy neurites) in dopaminergic neurons of the substantia nigra. Occupational exposure to specific metals, especially manganese, copper, lead, iron, mercury, zinc, aluminum, appears to be a risk factor for Parkinson's disease based on epidemiological studies. Elevated levels of several of these metals have also been reported in the substantia nigra of Parkinson's disease subjects. We examined the effect of various metals on the kinetics of fibrillation of recombinant alpha-synuclein and in inducing conformational changes, as monitored by biophysical techniques. Several di- and trivalent metal ions caused significant accelerations in the rate of alpha-synuclein fibril formation. Aluminum was the most effective, along with copper(II), iron(III), cobalt(III), and manganese(II). The effectiveness correlated with increasing ion charge density. A correlation was noted between efficiency in stimulating fibrillation and inducing a conformational change, ascribed to formation of a partially folded intermediate. The potential for ligand bridging by polyvalent metal ions is proposed to be an important factor in the metal-induced conformational changes of alpha-synuclein. The results indicate that low concentrations of some metals can directly induce alpha-synuclein fibril formation.

Subfields: Neurology, Physiology

View Paper: https://www.semanticscholar.org/paper/6336599b8b9126fded55c237e85d38010cbae4fb

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Citations in the corpus

• Ferroptosis, a newly characterized form of cell death in Parkinson's disease that is regulated by PKC. (2016, neutral): “…endogenous source of ROS (Youdim and Riederer, 2004); (iii) DA metabolites can react with iron and H2O2 to form the neurotoxic compound 6- hydroxydopamine (Napolitano et al., 2011) and (iv) iron increases the rate of α-synuclein fibril formation - a major event in PD (Uversky et al., 2001).”
• Copper in diseases and treatments, and copper‐based anticancer strategies (2009, background): “Protein-metal interactions appear to play a critical role in protein aggregation and are therefore likely to provide a link between the accumulation of aggregated proteins, oxidative damage of the brain, and neuronal cell loss in an age-dependent manner.(12,13) Actually, copper is also implicated in”
• Different Species of α-Synuclein Oligomers Induce Calcium Influx and Seeding (2007, background): “The influence of iron on in vitro aggregation of -syn has been reported by Uversky et al. (2001).”
• Human Health Risk Assessment for Aluminium, Aluminium Oxide, and Aluminium Hydroxide (2007, background): “However, such beneficial effects could be offset by the reported ability of aluminium to increase the rate at which amyloid peptides ( Kawahara et al, 1994 ; 2001 ; Mantyh et al, 1993 ), and other pathogenic proteins such as α-synuclein ( Uversky et al, 2001 ), to assemble into more stable and pat”
• Low dose mercury toxicity and human health. (2005, background): “…ajor constituent of intracellular protein inclusions (Le odies and Lewy neurites) in dopaminergic neurons o ubstantia nigra leading to parkinson’s (Uversky et al., 2001). oreover, low concentrations of cobalt and mercury are o induce oxidative stress, cell cytotoxicity and increase ecretion of…”