Alpha-Synuclein, lipids and Oxidative Stress: A cellular approach based on different dopaminergic models for Parkinson?s Disease

FALOMIR LOCKHART, LJ

La Plata

Congreso; 8th International Conference on Lipid Binding Proteins; 2013

INIBIOLP

Parkinson?s disease (PD) is the second most common neurodegenerative disorder. Its pathologic hallmark is the loss of dopaminergic neurons and the appearance of intracellular amyloid aggregates known as Lewy Bodies. Although the majority of PD cases are sporadic, some familial mutations are known and they may hold the key to unraveling the initial molecular triggers leading to neurodegeneration. Some of these clinical genetic alterations are linked to the SNCA gene that codes for the intrinsically disordered protein α-Synuclein (aSyn), the major component of the Lewy Bodies. Although the extensive focus on aSyn, little is known about its physiological functions. It´s apparent lack of structure when free in solution is balanced by a strong tendency to adopt an α-helix when bound to membranes, or a stable cross β-sheet in the amyloid aggregates. aSyn has been previously linked to FABPs in size and some partial sequence homology, but it shows little or none affinity for free fatty acids (FFA) in the unstructured forms. However, the preference for anionic phospholipid surfaces has been proved extensively. We have performed a systematic analysis of aSyn interaction with model membranes based on selective labeling of Cys-mutants spanning all aSyn sequence with new environment sensitive dyes. Furthermore, we have proved a concentration-dependent localization of aSyn in isolated mitochondria. This correlates with the metabolic alterations we found in patient-derived iPSCs reprogrammed into neuronal progenitors overexpressing aSyn due to a tandem-triplication of a portion of chromosome 4 that includes the SNCA gene. These cells also show difficulties differentiating and establishing a functional neurites´ network in culture conditions compared to a control line derive from a sibling. Our results support the hypothesis that aSyn overexpression is associated with a gain of toxic function in dopaminergic neurons, but also suggest that an impaired metabolism could be involved in the initial molecular events responsible of PD. Supported by Alexander von Humboldt Foundation, BMBF, MPG´s Toxic Proteins (Ger), ANPCyT, CONICET (Arg), and California Institute for Regenerative Medicine (USA).