α-Synuclein as a molecular link between Parkinson's disease and chronic kidney disease: insights into the kidney-brain axis.

α-synuclein (α-syn), a presynaptic protein encoded by the SNCA gene, is implicated in the pathogenesis of Parkinson's disease (PD) because of its tendency to misfold and form aggregates. Emerging evidence suggests that α-syn dysfunction may also affect peripheral organs, with chronic kidney disease (CKD) increasingly recognized as a potential comorbidity. This review critically examines current evidence on the molecular pathways linking PD and CKD through α-syn. α-Syn comprises an N-terminal lipid-binding domain, a non-amyloid component (NAC) region prone to aggregation, and a C-terminal domain that regulates conformational stability. Among the proposed mechanisms, mitochondrial dysfunction, oxidative stress, and impaired autophagy-lysosomal clearance represent the most consistently reported pathways across neuronal and renal systems, while activation of the renin-angiotensin system (RAS) has been implicated in more limited or context-dependent studies. Preclinical and limited clinical observations indicate that α-syn-associated processes may contribute to podocyte injury and fibrotic remodeling in renal tissue, whereas reduced α-syn expression has been suggested to compromise epithelial cell stability. These findings support the concept of a kidney-brain axis; however, the extent and directionality of this interaction remain incompletely defined. Novel α-syn-targeted therapies, including ENT-01, Cu(II)ATSM, ambroxol, and lipid-modulating strategies, are being investigated for their cross-organ efficacy, although most evidence currently derives from preclinical or early-phase studies. Importantly, key knowledge gaps persist, including the mechanisms underlying peripheral α-syn aggregation, the pathways of inter-organ communication, and the clinical validity of α-syn-based biomarkers. Overall, current evidence supports a potential role for α-syn as a contributing molecular link between neurodegenerative and renal dysfunction, rather than a definitive unifying mechanism, underscoring the need for integrated and evidence-driven diagnostic and therapeutic approaches.