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

FALOMIR LOCKHART LJ; OLIVEIRA LMA; ZAHNG HX; MAK S; ARNDT-JOVIN DJ; SCHUELE B; JOVIN TM

Baltimore

Congreso; Annual Meeting of the American Society of Neurochemistry 2012; 2012

ASN

Parkinson’s disease (PD) is a pro¬gressive neuro¬degenerative disorder pre¬sent in more than 1% of the population above 60 years. PD is histologically defined by in¬tra¬cellular amyloid aggregates of pro¬teins and lipids, and most clinical symptoms arise after the selective loss of dopaminergic neu-rons in the midbrain. The pro¬tein alpha-Synuclein (aSyn) is the most abundant component in these aggregates and has been identified as a key player in the develop¬ment of PD. Nevertheless, a compre¬hensive description of the relationship between amyloid aggregates and selective neu¬ronal death is still missing. Recent data poin¬t towards early in¬ter¬mediates as the main “culprits” to degene¬ration, rather than amyloid fibrils. Further¬more, oxidative stress and mitochondrial dysfunction are considered critical in the develop¬ment and the patho¬logy. Lipid and pro¬tein oxidation have also pre¬sent to play a central etiological role. We studied the modulation of the dopaminergic differentiation pathway of SH-SY5Y cells by lipids and studied their impact on the toxicity of dopamine and 6-hydroxy¬dopamine as oxidative stress pro¬moters. While cholesterol stabilized the dopaminergic phenotype, arachidonic acid stimulates aSyn ex¬pression. Nevertheless, together they seem to pro¬tect against dopamine aggression. Alternatively, we synthesized stable covalent oligo¬mers of aSyn, based on specific oxidation of Tyr residues of aSyn in vitro; which inhibited aggregation in vitro and showed increased toxicity on differentiated SH-SY5Y cells when applied extracellularly. More recently, the develop¬ment of patient-derived induced pluripotent stem cells (iPSCs) has opened a new range of possibilities for evaluating the relationship of aSyn, lipids and oxidative stress in a well-defined genetic background from clinical cases affected with the disease. We have found that iPSC-derived neu¬ronal cultures from PD patients seem to be more sensitive to stress conditions and to pre¬sent higher levels of modified aSyn, particularly the phos¬phorylated form that accumulates in the nuclei. Other targets of investigation are the stress of organelles like mitochondrias, lysosomes and auto¬phagosomes.