Biphasic Temporal Remodeling Of The Proteome In A Polyglutamine-Expanded Huntingtin In Vitro Aggregation Cell Model: From Early Rna-Regulatory Compensation To Selective Mitochondrial Energy Failure
Abstract
Huntington’s disease (HD) is caused by a polyglutamine-expanded huntingtin protein that exerts progressive cellular toxicity. However, the temporal sequence of pathogenic, particularly early and reversible versus late and irreversible events remain incompletely defined, despite their distinct therapeutic implications. To delineate this trajectory, we profiled the proteome of a huntingtin-expressing cell model at early (72 h) and late (144 h) stages. Rather than a linear progression, pathogenicity unfolded in two discrete phases. At the early stage, cells exhibited a broad activation of RNA-processing, splicing, and protein-synthesis machinery, consistent with an adaptive response aimed at preserving gene-expression fidelity under stress. By the late stage, this compensatory program had collapsed, giving rise to a dominant failure in mitochondrial energy metabolism. Notably, 85% of proteins altered at both time points reversed direction of change between stages, indicating that mutant huntingtin reprograms cellular function wholesale rather than amplifying a fixed set of perturbations. Detailed analysis of mitochondrial respiratory complexes revealed that terminal ATP-generating components (cytochrome c oxidase and ATP synthase) were severely affected, whereas upstream electron-transport elements were retained or upregulated. Leveraging this proteomic map, we applied an AI-assisted, direction-aware drug repurposing strategy. Of 1,712 differentially expressed proteins, 498…
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Evidence Hub reads this as a preprint, done in cell cultures (in vitro), not in people. Its evidence level is 5 of 5 (Very low · case / narrative / animal / in vitro / in silico). Case reports, narrative reviews, and animal, cell or computer-model studies give the weakest evidence for human health.
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