Parkinson's disease as a disorder of synaptic raft integrity: A unified explanation for motor subtypes and non-motor symptoms.

Parkinson's disease (PD) has traditionally been attributed to nigrostriatal dopaminergic neurodegeneration; however, neuronal loss alone does not adequately account for the diversity of motor subtypes, variability in treatment responses, or the wide spectrum of non-motor symptoms. Converging evidence from both raft-focused and network-level lipidomic studies suggests a shared upstream membrane dysfunction characterized by coordinated disruptions in raft-enriched lipids. In this conceptual review, I propose that PD may be conceptualized as a disorder of synaptic lipid raft integrity ("raftopathy") affecting both dopaminergic and non-dopaminergic systems. Within this framework, clinical heterogeneity may be understood along a multidimensional spectrum reflecting the relative contributions of presynaptic and postsynaptic dysfunction, as well as involvement of non-dopaminergic networks. Presynaptic raft disruption may preferentially impair dopamine release and contribute to akinetic-rigid phenotypes with limited pharmacological responsiveness, whereas postsynaptic raft instability may increase receptor signaling variability, potentially underlying tremor-dominant features, wearing-off phenomena, and dyskinesia. Furthermore, neuronal degeneration is hypothesized to represent a downstream consequence of sustained synaptic dysfunction rather than the primary initiating event. This raft-centered framework may provide a conceptual basis for developing therapeutic strategies that extend beyond dopamine replacement, particularly for addressing treatment-related complications and non-motor symptoms.