Neurotoxicity of Endogenous Neurotoxin Salsolinol in Parkinson's Disease.

Abstract

Salsolinol (SAL), an endogenous neurotoxin 1-methyl-6,7-dihydroxy-1,2,3,4- tetrahydroisoquinoline, is a dopamine metabolite that has been implicated in the pathogenesis of Parkinson's disease (PD) due to its selective toxicity toward dopaminergic (DA) neurons. Experimental studies have demonstrated that SAL induces DA neuronal injury both in vitro and in vivo, thereby contributing to the PD pathogenesis. Given its specificity for nigral DA neurons, SAL serves as a more relevant model for studying PD-associated brain waste clearance and neurotoxicity, as it recapitulates the progressive nature of the disease. Emerging evidence indicates that SAL exerts its neurotoxic effects primarily through the induction of oxidative stress and regulated cell death in DA neurons. With the escalating global burden of PD and unmet need for therapies targeting multifactorial mechanisms, the dual role of SAL as both a dopamine derivative and mediator of protein aggregation links metabolic dysfunction to neurodegeneration, positioning it as a pivotal target for understanding sporadic PD and therapeutic development. In this review, we summarize current knowledge on the molecular mechanisms underlying SAL-induced neurotoxicity and its pathophysiological role in PD. By elucidating these mechanisms, this review provides valuable insights for future research in uncovering underestimated molecular targets for therapeutic intervention in PD.