Background/Objectives: Increasing evidence reveals the likely peripheral etiology of Parkinson’s disease; however, the mechanistic insight into α-Synuclein aggregation in the periphery remains unclear. This study aimed to explore the effect of abnormal expression of renalase on dopamine metabolism, toxic DOPAL generation, and subsequently, α-Synuclein aggregation. Methods: Blood pressure (BP) was monitored while changing the body position of rats; the serum level of renalase was detected by ELISA; the mRNA/protein of renalase and α-Synuclein were determined by qRT-PCR/Western blot; DOPAL was measured using HPLC; renalase distribution was explored by immunostaining; cell viability and ultrastructure were examined by TUNEL and electron microscopy, respectively. Results: The results showed that, in PD model rats, the serum level of renalase was increased time-dependently with up-regulated renalase gene/protein expression in the nodose ganglia, nucleus tractus solitarius, and heart; a reduced dopamine content was also detected by the renalase overexpression in PC12 cells. Strikingly, up-regulated renalase and orthostatic BP changes were observed before the behavioral changes in the model rats. Meanwhile, the levels of DOPAL and α-Synuclein were increased time-dependently. Intriguingly, the low molecular weight of α-Synuclein declined coordinately with the increase in the higher molecular weight of α-Synuclein. Clear ultrastructure damage at the cellular level supported the notion of molecular findings. Notably, the α-Synuclein aggregation-induced impairment of the axonal transport function predates neuronal degeneration mediated by renalase overexpression. Conclusions: Our results demonstrate that abnormal peripheral dopamine metabolism mediated by overexpressed renalase promotes the DOPAL-induced α-Synuclein and leads to baroreflex afferent neuronal degeneration and early autonomic failure.