alpha-Synuclein and oxidative stress, a quest looking for the trigger of Parkinson’s Disease

FALOMIR LOCKHART LJ; BORSARELLI CD; OSTATNÁ V; FAUERBACH JA; PALECEK E; JARES ERIJMAN EA; JOVIN TM

Bonn

Conferencia; 1st Bonn Humboldt Award Winners Forum; 2011

Alexander von Humboldt Foundation

Parkinson’s disease (PD) is a progressive neurodegenerative condition present in more than 1% of the population above 60 years. PD is histologically defined by intracellular amyloid aggregates of proteins and lipids and most clinical symptoms arise after the selective loss of dopaminergic neurons of the substantia nigra. The protein alpha-Synuclein (aSyn) is the most abundant component in the amyloid aggregates and has been identified as a key player in the development of PD. Nevertheless, a comprehensive description of the relationship between amyloid aggregates and selective neuronal death is still missing. New data point towards early intermediates rather than amyloid fibrils as the “culprits”. Furthermore, oxidative stress is considered critical and lipid oxidation has been suggested to have also a central etiological role. We established a method for synthesizing stable oligomers of different order by specific oxidation of Tyr residues (diTyr crosslinking) of aSyn. Spectroscopic, electrochemical and biochemical characterization demonstrated the novel properties of these species that may be leading reduced aggregation in vitro and increased toxicity upon exposure to differentiated SH-SY5Y cells. We also investigated the influence of Arachidonic acid (AA) and Cholesterol (Chol) on the retinoic acid-induced differentiation of SH-SY5Y cells and studied the toxicity of Dopamine and 6-Hydroxydopamine as oxidative stress promoters. Chol stabilizes the dopaminergic phenotype during differentiation and AA stimulates aSyn expression. Together, Chol and AA protect against dopamine aggression. Although its physiological functions are still poorly understood, aSyn apparently participates in intracellular vesicular trafficking and in neurotransmitter release. Our results indicate that the interrelationships between aSyn, lipids and oxidative stress constitutes a triad presumably at the center of the molecular trigger mechanism(s) and/or process(es) leading to PD.