Overexpression of α-Synuclein Alters The Nanoscopic Organisation of Presynaptic Proteins

Parkinsons Disease (PD) is characterised by accumulation of α-synuclein (α-Syn), but how elevated α-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 α-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 α-Syn were observed without changes to bouton structure. Additionally, increases of both α-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 α-Syn perturbs AZ components whilst presynaptic structure is preserved. Our study supports growing evidence that increased α-Syn disturbs presynaptic function potentially through a MYCBP2-ELKS axis, a mechanism which may provide a valuable target for PD therapeutics.