A new paradigm in Parkinson's disease: kidney-origin α-synuclein pathology driven by PKC signaling and aurothioglucose.

Abstract

Protein Kinase C (PKC), a zinc-dependent signaling enzyme essential for cellular homeostasis, has recently emerged as a critical regulator of α-synuclein (α-Syn) dynamics beyond the central nervous system. Growing evidence suggests that PKC may contribute to α-Syn accumulation in kidney cells through multiple converging mechanisms, including direct phosphorylation of α-Syn, which promotes its aggregation, disruption of the autophagy-lysosome pathway leading to impaired protein clearance, and amplification of oxidative stress and inflammatory responses that enhance α-Syn toxicity. In a paradigm-shifting discovery, recent findings from Wuhan University indicate that Parkinson's disease (PD) pathology may originate in peripheral organs such as the kidneys rather than the brain. Abnormal α-Syn aggregates have been identified in renal tissues of affected individuals, and experimental models demonstrate that compromised kidney function facilitates the systemic spread of these toxic proteins to the brain, potentially initiating neurodegeneration. Notably, α-Syn accumulation has also been observed in patients with chronic kidney disease in the absence of neurological symptoms, suggesting a potential early reservoir function of the kidneys. In this context, aurothioglucose (ATG), a gold-based anti-inflammatory agent, emerges as a promising therapeutic candidate due to its ability to modulate PKC signaling, attenuate inflammation, and restore proteostatic balance. This review highlights a novel kidney-brain axis in PD pathogenesis and proposes PKC-targeted interventions, including ATG, as potential strategies for early disease modification.