A meta-analysis resolves the huntingtin interactome into coactivator losses and a robust proteostatic and synaptic gain network

Abstract

Transcriptional dysregulation and proteostatic collapse are cardinal yet mechanistically separate features of Huntington disease (HD), and how the polyglutamine (polyQ) expansion in huntingtin (HTT) rewires its interactome to produce both remains unresolved. We integrated four published HTT affinity-proteomics datasets and contrasted wild-type and polyQ-expanded HTT within one Bayesian model (BO_SCPLOWAYESC_SCPLOWIO_SCPLOWNTERACTOMICSC_SCPLOW). Of 4,338 proteins, 275 were condition-dependent: the expansion strips HTT of the transcription-activation machinery (Mediator, the ASCOM H3K4-methyltransferase, CREBBP, CDK9) while gaining contacts with the 26S proteasome, HSP70 chaperones and a synaptic and actin-cytoskeletal network, around an intact chaperonin-HAP40 core. This picture emerges only from integration: the datasets overlap so little that a "reproducible in [≥] 2 studies" consensus would recover just [~] 21% of the high-confidence interactors. By reconciling HDs transcriptional and proteotoxic arms within one quantitative interactome, this loss-plus-gain model recasts two historically separate disease mechanisms as complementary and nominates prioritised interfaces (HTT-Mediator/ASCOM, HTT-proteasome) for validation and therapeutic targeting.