DOPAL initiates αSynuclein-mediated impaired proteostasis in neuronal projections leading to enhanced vulnerability in Parkinson's disease.
Dopamine dyshomeostasis has been acknowledged to be among the determinants of nigrostriatal neuron degeneration in Parkinsons disease (PD). Several studies in experimental models and postmortem PD patients underlined increasing levels of the aldehydic dopamine metabolite 3,4-dihydroxyphenylacetaldehyde (DOPAL), which is highly reactive towards proteins. DOPAL has been shown to covalently modify the presynaptic protein Synuclein (Syn), whose misfolding and aggregation represent a major trait of PD pathology, triggering Syn oligomerization in dopaminergic neurons. Here, we demonstrated that DOPAL elicits Syn neuronal accumulation and hampers Syn clearance at synapses and the soma. By combining cellular and in vivo models, we provided evidence that DOPAL-induced Syn buildup lessens neuronal resilience, compromises synaptic integrity, and overwhelms protein quality control pathways, specifically at neuronal projections. The resulting progressive decline of neuronal homeostasis leads to dopaminergic neuron loss and motor impairment, corroborating the Syn-DOPAL interplay as an early event in PD neurodegeneration.