Gut‐Derived α‐Synuclein Condensates in Parkinson's Disease: Linking Liquid–Liquid Phase Separation, Blood Dissemination, and Chemical Biology

Two advances have reshaped our understanding of α‐synuclein (αSyn) in Parkinson's disease (PD). First, αSyn can assemble through liquid–liquid phase separation (LLPS) and related condensation pathways, forming condensates that mature into Lewy‐body‐like assemblies. Although conventional crowding‐driven LLPS requires supraphysiological protein concentrations, membrane‐templated surface condensation has been reported in vitro at ~10 nM, making this pathway plausible in the lipid‐rich, electrically active enteric nervous system (ENS). Second, seeding‐competent αSyn is detectable in blood before motor onset using seed‐amplification assays. This review asks whether condensate‐derived αSyn generated in the gut constitutes a blood‐borne seed population that is systematically underrepresented by fibril‐biased assays. We evaluate each step of the proposed pathway, including gut‐specific LLPS triggers, release into and survival within the circulation, blood–brain barrier (BBB) traversal, and clinical detection, while distinguishing established evidence from indirect inference and testable hypotheses. Many of these questions are now experimentally accessible. Molecular rotors detect condensates through microviscosity rather than cross‐β structure, condensate‐stage modulators have emerged, and receptor‐interception strategies such as bemcentinib provide opportunities for mechanistic interrogation. Together, these advances position chemical biology to determine whether condensate‐derived seeds contribute to PD pathogenesis.