Combating Deleterious Phase Transitions in Parkinson's Disease

摘要

Parkinson's disease（PD） is a progressive neurodegenerative disease pathologically defined by the selective loss of dopaminergic neurons in the substantia nigra pars compacta and the aberrant accumulation of misfolded α-synuclein（α-syn） into Lewy bodies（LBs） and Lewy neurites（LNs）. Emerging evidence indicates that α-synuclein aggregation is preceded by neurotoxicity and that the earliest nucleation events are mediated by liquid–liquid phase separation（LLPS）, a physicochemical process through which intrinsically disordered proteins demix into condensed liquidlike droplets. Although the molecular determinants governing α-syn LLPS remain incompletely understood, disease-associated mutations, post-translational modifications, truncation events, and environmental factors have all been shown to perturb droplet dynamics, promoting a transition from reversible liquid states to irreversible amyloid aggregates. This review synthesizes current mechanistic insights into how the primary sequence and structural topology of α-synthe amphipathic N-terminal domain, the amyloidogenic NAC region, and the acidic C-terminal tailcooperate to drive and regulate LLPS. We critically evaluate how familial point mutations（A30P, E46K, H50Q, A53T/E） destabilize electrostatic networks that normally restrain phase separation, thereby accelerating fibrillization and neuronal toxicity. Conversely, we discuss how targeted silencing of pathogenic variants with antisense oligonucleotides（ASOs） lowers α-syn concentration below the critical saturation threshold, suppressing both LLPS and downstream aggregation in rodent and non-human primate models. At the C-terminus, we dissect the modulatory impact of phosphorylation（pS129 and pY125）, ubiquitination, oxidation, nitration, and SUMOylation on droplet viscosity and amyloid conversion, highlighting the therapeutic potential of phospho-site-specific kinase inhibitors and molecular chaperone cofactors such as CHIP. We further examine how calpain-and caspase-1-mediated truncation removes negative charges that normally shield the NAC domain, thereby lowering the energy barrier for LLPS and generating aggregation-prone species detectable in prodromal gut and appendix biopsies. Finally, we outline how divalent metal ions(Ca²⁺, Fe²⁺, Mn²⁺) compress the Debye length, facilitate cross-β contacts, and reduce the saturation concentration required for droplet nucleation, and we summarize pre-clinical studies in which metal chelators restore physiological droplet dynamics. Collectively, these data position α-syn LLPS as a tractable therapeutic node upstream of irreversible proteinopathy. We propose an integrated intervention paradigm that combines（i） allele-specific gene silencing to limit α-syn supply,（ii） small-molecule or biological modulators of post-translational status to re-establish droplet homeostasis, and（iii） chelation or antioxidant strategies to neutralize environmental precipitants. By translating mechanistic biophysics into precision neurology, such multi-pronged approaches promise to arrest or even prevent the neurodegenerative cascade in Parkinson's disease and related synucleinopathies.

关键词

α-syn / liquid–liquid phase separation(LLPS) / pathophysiology mechanism / Parkinson's disease(PD)