{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n Ataxin‑1 (ATXN1) is a nuclear protein that normally functions as a transcriptional regulator by assembling into large, stable multiprotein complexes with partners such as the transcriptional repressor Capicua and splicing modulators like RBM17, thereby fine‐tuning gene expression programs essential for cerebellar development and neuronal homeostasis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": " The phosphorylation state of ATXN1—most notably at serine 776—is critical for its normal function, as this post‐translational modification regulates its binding to essential interactors such as Capicua; loss of Ser776 phosphorylation diminishes these interactions and concomitantly reduces neurotoxicity."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": " In spinocerebellar ataxia type 1 (SCA1), expansion of the polyglutamine tract within ATXN1 not only promotes aberrant interactions—for example, favoring complex formation with RBM17—but also attenuates its formation of native complexes with Capicua, thereby initiating a dual pathogenic mechanism that features both a toxic gain-of-function and a partial loss of normal function."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}, {"type": "fg_f", "ref": "6"}, {"type": "fg_f", "ref": "5"}, {"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": " Moreover, ATXN1 levels are exquisitely dosage sensitive and are controlled by protein quality mechanisms—including ubiquitination by CHIP—and by post-transcriptional regulators such as PUMILIO1, whereby even modest increases in ATXN1 levels can exacerbate neurodegeneration."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": " Collectively, these studies underscore that the neurodegenerative pathology observed in SCA1 arises not solely from the acquisition of new toxic functions by the mutant protein, but also from a disruption of its normal, developmentally critical roles in modulating transcription and interacting with key cofactors."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": " Consequently, therapeutic strategies aimed at restoring ATXN1’s normal protein interactions or mitigating its aberrant accumulation may offer promise in slowing or halting disease progression.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Kei Watase, Edwin J Weeber, Bisong Xu, et al. 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