Molecular mechanisms of Microcystin-LR decreasing dopamine release by binding VPS35 and clinical correlation between Microcystin-LR exposure and Parkinson's disease.

Microcystins (MCs) are a class of monocyclic heptapeptide natural toxins produced by freshwater cyanobacteria. They can enter the human body via contaminated water or food. Currently, MCs are recognized by the World Health Organization as health risk factors, with microcystin-leucine-arginine (MC-LR) being the most prevalent and toxic. Our previous research demonstrated that chronic MC-LR exposure reduced dopamine (DA) release from dopaminergic neurons in the substantia nigra, causing Parkinson's disease (PD)-like motor dysfunction in mice. Motor dysfunction is closely linked to reduced DA levels. However, the molecular mechanism by which MC-LR reduces DA release remains unknown. Furthermore, whether serum MC-LR levels are a risk factor for PD in general population and correlates with patients' motor dysfunction warrants further investigation. After DA is synthesized within dopaminergic neurons, it is stored in synaptic vesicles through vesicular monoamine transporter 2 (VMAT2). The stability of VMAT2 requires retromer complex and its core component VPS35. We demonstrate that MC-LR directly binds to VPS35, destabilizing the retromer and leading to increased VMAT2 lysosomal degradation. Concurrently, MC-LR inhibits the Wnt1/β-catenin signaling pathway by downregulating Wnt1, further reducing VPS35 transcription and VMAT2 levels. These effects collectively reducing dopamine levels. To further evaluate the clinical relevance between MC-LR and PD, a cross-sectional study in a human population was conducted. The results showed that elevated serum MC-LR levels are associated with an increased PD risk and motor dysfunction. Integrating evidence from in vivo, in vitro, and human population studies, this study establishes a link between MC-LR exposure and PD.