Lipids, alpha-Synuclein and Oxidative Stress. Searching for the Trigger of Parkinson’s Disease

FALOMIR LOCKHART LJ; FUENTES F; MARTINEZ JH; BORSARELLI CD; OSTATNÁ V; FAUERBACH JA; NEUMANN D; JAKOBS S; PALECEK E; JARES ERIJMAN EA; JOVIN TM

Göttingen

Conferencia; Neurizons 2011; 2011

MMPIbpc-MPIem-Georg August University

Parkinson 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 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 and other neuropathies. 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. Here, we analyzed 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 the differentiation and AA stimulates aSyn expression. Together, Chol and AA protect against dopamine aggression. Furthermore, controlled and specific oxidation (diTyr crosslinking) of aSyn leads to species with higher toxicity than unmodified monomer on differentiated SH-SY5Y. Here we also report the binding of aSyn to purified mitochondria, which colocalized with TOM-20 outer membrane marker, as observed by STED Microscopy (see also poster Shvadchak et al.). Finally, different fatty acids slow the aggregation of aSyn in vitro and stabilize some intermediate oligomeric species. aSyn specific functions are still not clearly understood, but is supposed to participate in neurotransmitter release. Our results indicate that the interrelationship between aSyn, lipids (phospholipid membranes and fatty acids) and oxidative stress constitutes a triad that is presumably in the center of the molecular trigger mechanism and/or the process leading to PD.