Blocking the aerobic/energy source in neurons via SGLTs inhibits /delaying Parkinson’s disease biomarker α-synuclein transmission/ propagation

Progressive loss of dopaminergic neurons in the substantia nigra (SN) pars compacta (SNpc) and the formation of cytoplasmic inclusions containing misfolded α-synuclein (α-syn), Lewy bodies (LBs) like characteristics are two major neuropathological hallmarks of Parkinson Disease (PD) Which is the second most common neurodegenerative disease. PD and Diabetic mellitus (DM) share potential contributing factors and have overlapping pathology. Studies have unveiled a crucial connection between PD and DM. DM, distinguish by impaired glucose metabolism and subsequent hyperglycemia. The elevated risk of developing cognitive abnormalities in individuals with impaired glucose metabolism has been well documented. Hyperglycemia, a common pathogenesis in T2DM, has been shown to contribute to the onset of α-syn pathology in neurons and oligodendrocytes. Phosphorylated α-syn inclusions have been found in pancreatic β cells of T2DM subjects, indicating the existence of PD-related peripheral pathology in DM. But due to the complicated effect of glucose transporter on PD induced dopaminergic degeneration still not well understood. Here, we demonstrate that A53T mutated cell and α-syn fibrils induce active glucose energy transporter SGLTs activation in neurons which increased the uptake of α-syn into neurons. Furthermore, the inhibition of SGLTs inhibits the α-syn uptake and the formation of lewy body-like inclusions. These results demonstrated a new therapeutic approach for PD.