Overexpression of α-Synuclein Alters The Nanoscopic Organisation of Presynaptic Proteins
Watson, I. A.; Bridi, J. C.; Hanger, D. P.; Hirth, F.; Srivastava, D. P.
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Parkinsons Disease (PD) is characterised by accumulation of -synuclein (-Syn), but how elevated -Syn alters presynaptic architecture during prodromal phases of the disease remains unclear. We investigated presynaptic morphology and two key presynaptic proteins: MYCBP2; and the Active Zone (AZ) protein ELKS. Primary rat cortical neurons were transfected with wildtype -Syn, or the familial A30P mutant, and nanoscopic changes to bouton morphology and protein localisation were investigated using super-resolution microscopy. Variant specific accumulation patterns for overexpressed -Syn were observed without changes to bouton structure. Additionally, increases of both -Syn variants affected presynaptic proteins, decreasing MYCBP2 puncta count and intensity, and reducing ELKS protein density. Since MYCBP2 potentially regulates ELKS, these findings suggest that elevated -Syn perturbs AZ components whilst presynaptic structure is preserved. Our study supports growing evidence that increased -Syn disturbs presynaptic function potentially through a MYCBP2-ELKS axis, a mechanism which may provide a valuable target for PD therapeutics.
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