Convergent Astrocytic Failure in Parkinson's Disease: A System-Level Model of Pathogenesis and Treatment.
Convergent Astrocytic Failure in Parkinson's Disease: A System-Level Model of Pathogenesis and Treatment.
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Original abstract
A paradigm shift from a purely neurodegenerative disorder to a multicellular failure of the neuroglial unit has fundamentally redefined Parkinson's disease (PD). This review synthesizes compelling evidence that positions astrocyte dysfunction, or astrocytopathy, as a central and active driver of pathogenesis, extending far beyond a passive bystander role. We delineate how pathological α-synuclein triggers a vicious cycle of astrocytic failure, encompassing impaired proteostasis via ubiquitin-proteasome and autophagy-lysosomal pathways, glymphatic system collapse due to aquaporin-4 (AQP4) depolarization, and chronic neuroinflammation driven by microglial crosstalk and NLRP3 inflammasome activation. This core triad is exacerbated by critical deficits in metabolic support, including disruption of the astrocyte-neuron lactate shuttle, aberrant lipid droplet metabolism, and failure in mitochondrial transfer. Furthermore, we integrate emerging systemic axes, demonstrating how peripheral gut dysbiosis, via the microbiota-gut-astrocyte (MGA) axis, and central circadian rhythm disruption converge to amplify central glial pathology. Critically, the present reframing unveils novel, cell-type-specific therapeutic avenues. We evaluate strategies to restore neuroprotection by targeting AQP4 polarization, modulating GLP-1 receptor signaling to mitigate inflammation, employing senolytics to clear dysfunctional glia, and utilizing gene therapy to engineer astrocytes as trophic bio-factories. By deconstructing PD as a disorder of astrocyte-neuron crosstalk, this review provides a roadmap for next-generation, disease-modifying therapies aimed at rescuing glial homeostasis to halt progression, moving beyond symptomatic dopamine replacement to address the core pathophysiology.