In vivo NMR characterization of unsaturated fatty acids in a C. elegans model of Parkinson Disease

GUASTAFERRI, FLORENCIA; DELPRATO, CARLA; HERNANDEZ-CRAVERO, BRUNO; LOMBARDO, VERÓNICA A.; VRANYCH, CECILIA; DE MENDOZA, DIEGO; BINOLFI, ANDRES

Rosario

Congreso; L Reunión Anual de la Sociedad Argentina de Biofísica.; 2022

Alpha-Synuclein (aSyn) is an intrinsically disordered protein widel y expressedthroughout the human brain. Aggregates of aSyn are the primary protein component of Lewy bodies, amyloid deposits found in dopaminergic neurons of the substantia nigra of Parkinson Disease (PD) patients. While it’s well known that misfolded aSyn has pathogenic properties that contribute to disease progression, the molecular mechanisms which cause aSyn to misfold are not clearly understood. Numerous studies showed that lipids can induce and/or accelerate the disease-associated misfolding of aSyn. Unsaturated fatty acids (UFAs), in particular, interact with aSyn in vitro and in vivo and this interaction may be implicated in PD pathogenesis. In fact, UFAs may also be regulated by aSyn in disease given that elevated levels of UFAs are observed in soluble lipid fractions of PD brain.To gain insight about the interaction between UFAs and aSyn as well as its role in the onset of PD it is necessary to characterize this association with high resolution in a context that accurately recapitulates the biochemical changes that occur within an organism. Accordingly, we use novel in vivo multidimensional NMR methodologies in live Caenorhabditis elegans that overexpress human, tag-free aSyn. C. elegans shares over 80% genetic homology with humans including genes that are linked to disease and has been established as a useful model for PD. Also, its small size, high reproductive rate and low cost of maintenance are very advantageous. We have developed an efficient technique to enrich nematodes with NMR active isotopes and obtained high resolution multidimensional NMR spectra in control and aSyn overexpressing worms to study how the protein modifies the worm lipid profile at molecular resolution. This approach allows us to study the effects of aSyn on lipids composition and behavior within the native environment of a live animal.