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

LISANDRO J. FALOMIR LOCKHART; F. FUENTES; J.H.MARTINEZ; C.D. BORSARELLI; V. OSTATNÁ; JONATHAN A. FAUERBACH; E. PALECEK; S. JAKOBS; E.A. JARES‐ERIJMAN; T.M. JOVIN

Goettingen

Conferencia; 4th Biennial Neuroscience Conference - Neurizons: From Molecules to Mind, making sense of the Brain; 2011

Parkinson’s Disease (PD) is a progressive neurodegenerative condition present in more than 1% of the population older than 60 years. The clinical picture is characterized by motor symptoms, memory loss, reduction or loss of sense of smell and sleep disorders that mostly arise after selective loss of dopaminergic neurons. Synucleopathies, like PD, are histologically defined by amyloid aggregates of proteins and lipids, known as Lewy Bodies, of which a‐Synuclein (aSyn) is the most abundant components (Figure 1). Nevertheless a comprehensive description that explains the relationship between the amyloid aggregates and the selective cell death is still to be achieved, specially because the cellular toxic species have not been identified. New data point to the early aggregates oligomers) rather the final fibrillar amyloid structures as the “culprits”. We recently introduced multiparametric ESIPT dyes for the detection of these intermediates [1,2], which are not reported by ThioflavinT, the classical probe for mature amyloid fibrils. Genetic alterations play a role in the expression levels and the aggregation of aSyn. Nevertheless, the factors that triggers this procedure are mostly not understood. An underplaying oxidative process, involving Dopamine related metabolites and linked to mitochondrial (dys)functionality (Figure 2), seems to be involved. The functions of aSyn are still unknown, but it is supposed to have the capacity to adopt multiple spatial configurations in order to sense the presence of different interacting partners that could stabilize (or disrupt) its normal functions. aSyn binds free fatty acids (FAs) [3,4] and associates with phospholipid membranes [5,6]. Here we report our latest results regarding the effects of the lipid environment on the aggregation of aSyn in vitro, as well as the importance of lipids on the differentiation of SH‐SY5Y, as a model for functional assays related to PD. We also analyzed the modulation of aSyn aggregation by different FAs. Finally, we studied the specific interaction of aSyn with purified Mitochondria as a model for natural membranes. Furthermore we study the phenotypical changes along the Retinoic Acid‐induced differentiation of SH‐SY5Y cells in the presence of Cholesterol and/or Arachidonic Acid (20:4, n‐6), and the relative toxicity induced by catecholamines on differentiated cells.