Work

Cryo-EM structures of human α-synuclein filaments reveal the molecular basis of PET tracer ACI-12589 recognition

Year: 2026

Type: preprint

Abstract: Misfolded α-synuclein adopts distinct amyloid architectures across synucleinopathies, complicating the development of PET tracers for in vivo detection. Here, we used cryo-EM to determine how the clinically evaluated tracer ACI-12589 recognizes disease-derived α-synuclein filaments isolated from human brain. In MSA type I and II filaments, ACI-12589 occupies a conserved C-terminal cleft in protofilament A, forming a diagonal array stabilized by hydrogen bonds and cooperative aromatic stacking without detectable backbone rearrangement. Recognition of PD filaments was strongly architecture dependent: no ordered ligand density was observed in singlet Lewy folds from idiopathic PD or SNCA H50Q-associated PD, whereas ACI-12589 bound an exposed β-sheet surface in the G51D dimerised Lewy fold in a geometry distinct from that observed in MSA. These structures reveal the molecular basis of fold-dependent tracer recognition and provide a framework for interpreting variable imaging signals and developing next-generation α-synuclein PET agents.

Source: Research Square

DOI: 10.21203/rs.3.rs-11652509/v1

Authors: Yang Yang, Katelyn Ernst, Hongwei Zhang, Francesca Capotosti, Patrick Cullinane, Henry Houlden, Huw Morris, Airi Tarutani, Kazuko Hasegawa, Masato Hasegawa, Zane Jaunmuktane

Institutions: Van Andel Institute, AC Immune (Switzerland), UCL Queen Square Institute of Neurology, National Hospital for Neurology and Neurosurgery, University College London, Tokyo Metropolitan Institute of Medical Science, National Sagamihara Hospital

Language: English

Topic: Parkinson's Disease Mechanisms and Treatments

Subfield: Clinical Neurology

Field: Medicine

Domain: Health Sciences

Open Access status: green

OpenAlex ID: W7225821953

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