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<p>Spinocerebellar ataxias (SCAs) are a large and heterogeneous group of inherent neurodegenerative diseases. A select group of SCAs are caused by abnormal CAG repeat expansions within the coding region of specific genes (polyQ SCAs). These alterations result in the synthesis of mutant proteins that carry an expanded tract of glutamine residues, which confers on them a toxic gain-of-function that disrupts multiple cellular processes, ultimately resulting in selective neuronal death. PolyQ SCAs are characterized by a core set of clinical features, including progressive cerebellar ataxia, motor incoordination, and neurodegeneration affecting the cerebellum and related neural circuits. At the molecular level, polyQ tracts have been shown to promote protein misfolding and aggregation, which in turn leads to cellular toxicity. Each SCA exhibits a distinctive pattern of cellular vulnerability, clinical progression, and neuropathology; therefore, the development of experimental models has been pivotal in elucidating disease mechanisms and facilitating translational research. In this review, we summarize the main experimental models utilized to study polyQ SCAs. These models include: (1) cellular systems that allow rapid and controlled analysis of molecular toxicity; (2) patient-derived induced pluripotent stem cells, which preserve endogenous gene regulation and genetic backgrounds; (3) non-mammalian organisms such as <i>Drosophila melanogaster</i>, <i>Caenorhabditis elegans</i>, and zebrafish, which support genetic screening and medium-throughput studies; (4) murine models that reproduce in vivo motor deficits, cerebellar degeneration, and transcriptional alterations; and (5) non-human primates (NHPs), which closely resemble human brain structure and function. We discuss the strengths and limitations of each model and underscore their contributions to elucidating the pathophysiology of disease and promoting the development of molecular therapies for polyQ SCAs.</p>

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Experimental Models to Study Polyglutamine Spinocerebellar Ataxias: From Mechanisms to Therapeutic Developments

  • 期刊论文

  • 发表日期：

    2026年4月1日

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  • Vanessa Ruiz-Esparza-Palacios,
  • Fabiola V. Borbolla-Jiménez,
  • Aranza Meza-Dorantes,
  • Regina Villarreal-Ramírez,
  • Bulmaro Cisneros,
  • Jonathan J. Magaña

摘要

Spinocerebellar ataxias (SCAs) are a large and heterogeneous group of inherent neurodegenerative diseases. A select group of SCAs are caused by abnormal CAG repeat expansions within the coding region of specific genes (polyQ SCAs). These alterations result in the synthesis of mutant proteins that carry an expanded tract of glutamine residues, which confers on them a toxic gain-of-function that disrupts multiple cellular processes, ultimately resulting in selective neuronal death. PolyQ SCAs are characterized by a core set of clinical features, including progressive cerebellar ataxia, motor incoordination, and neurodegeneration affecting the cerebellum and related neural circuits. At the molecular level, polyQ tracts have been shown to promote protein misfolding and aggregation, which in turn leads to cellular toxicity. Each SCA exhibits a distinctive pattern of cellular vulnerability, clinical progression, and neuropathology; therefore, the development of experimental models has been pivotal in elucidating disease mechanisms and facilitating translational research. In this review, we summarize the main experimental models utilized to study polyQ SCAs. These models include: (1) cellular systems that allow rapid and controlled analysis of molecular toxicity; (2) patient-derived induced pluripotent stem cells, which preserve endogenous gene regulation and genetic backgrounds; (3) non-mammalian organisms such as Drosophila melanogaster, Caenorhabditis elegans, and zebrafish, which support genetic screening and medium-throughput studies; (4) murine models that reproduce in vivo motor deficits, cerebellar degeneration, and transcriptional alterations; and (5) non-human primates (NHPs), which closely resemble human brain structure and function. We discuss the strengths and limitations of each model and underscore their contributions to elucidating the pathophysiology of disease and promoting the development of molecular therapies for polyQ SCAs.