α-Synuclein (α-syn) protein adapts various conformations ranging from monomeric to insoluble oligomeric/fibrillar forms based on the environmental factors, genetic mutations and its overexpression. Under physiological conditions it regulates synaptic vesicular trafficking, neurotransmitters release, synaptic transmission, etc. Misfolded α-syn protein, oligomers/fibrils form the main constituents of Lewy bodies, commonly observed in synucleinopathies. Present review emphasizes on various models of synucleinopathies—in vitro, yeast, invertebrates, fishes and their importance in high-throughput assays; as reasonable substitutes to mammals. While rodents share anatomical similarity with humans and mimic various pathomechanisms of Parkinson’s disease (PD), they lack any innate driver of PD. Also, non-human primates suitable for translational research are limited by high maintenance, extensive surgical and delivery procedures, although they can aid in drug discovery. Earlier findings on MPTP-induced differential susceptibility to PD in different mice strains from our lab showed reduction in substantia nigra pars compacta (SNpc) neuronal numbers, levels of tyrosine hydroxylase (TH), Nurr1, PitX3, calcium-binding and interneuronal proteins; increased expression of pro-apoptotic factors, pro-inflammatory cytokines; distinct organellar and vascular changes, etc. in C57BL/6 J strains. The CD1 and crossbreds showed better anatomical, molecular reserve and resilience against MPTP-elicited effects. Our previous human post-mortem studies on SNpc showed slight increase in α-syn expression with distinct Marinesco bodies in late middled-aged individuals with no decline in TH, contradicting the reports in Caucasians and suggesting subthreshold pathology in aging Asian Indians.