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<p>Huntington’s disease (HD) is an autosomal dominant neurodegenerative disease caused by an expanded cytosine–adenine–guanine (CAG) repeat (&gt; 36 repeats) in the huntingtin gene, leading to progressive motor dysfunction, cognitive decline, and psychiatric disturbances. Despite extensive research, the precise pathophysiological mechanisms underlying HD remain incompletely understood, necessitating reliable experimental models to investigate disease processes and identify therapeutic targets. Among preclinical models, 3-nitropropionic acid (3-NPA) is widely used to induce HD-like pathology in neuronal cell lines and animal models, including rats, mice, zebrafish, and avian species. In this review, we comprehensively discuss the molecular mechanisms underlying 3-NPA-induced neurotoxicity and its relevance to HD. 3-NPA primarily exerts its effects by irreversibly inhibiting succinate dehydrogenase (SDH), leading to mitochondrial dysfunction and energy failure. This metabolic disruption triggers oxidative stress, excitotoxicity, calcium dysregulation, and neuroinflammation, ultimately leading to selective striatal neurodegeneration and HD-like behavioral abnormalities. In addition to central nervous system effects, we also summarize the peripheral toxicities associated with 3-NPA, including skeletal muscle wasting, renal and hepatic dysfunction, ovarian stress, and cardiotoxicity. While 3-NPA effectively recapitulates several key pathological features of HD, it does not reproduce mutant huntingtin aggregation or progressive disease progression, representing a major limitation of this model. Overall, 3-NPA-induced pathology serves as a valuable experimental tool for studying specific aspects of HD, particularly mitochondrial dysfunction and related downstream pathways. Future studies integrating metabolic and genetic models will be essential to achieve a more comprehensive understanding of HD pathogenesis and to facilitate the development of effective therapeutic strategies.</p>

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3-Nitropropionic Acid–Induced Huntington’s Disease in Preclinical Models: Mechanisms, Peripheral Toxicities, Model Gaps, and Future Directions

  • 期刊论文

  • 发表日期：

    2026年1月1日

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  • Harikrishna Reddy Dontiboina,
  • Srikanth Yadava,
  • Venkata Prasuja Nakka,
  • Naresh Dumala,
  • Matte Kasi Viswanadh,
  • Chakravarthi Guntupalli,
  • Buchi N. Nalluri,
  • Narender Malothu,
  • Ganesh Yadagiri,
  • Lohitha Gujjari,
  • Kakarla Ramakrishna

摘要

Huntington’s disease (HD) is an autosomal dominant neurodegenerative disease caused by an expanded cytosine–adenine–guanine (CAG) repeat (> 36 repeats) in the huntingtin gene, leading to progressive motor dysfunction, cognitive decline, and psychiatric disturbances. Despite extensive research, the precise pathophysiological mechanisms underlying HD remain incompletely understood, necessitating reliable experimental models to investigate disease processes and identify therapeutic targets. Among preclinical models, 3-nitropropionic acid (3-NPA) is widely used to induce HD-like pathology in neuronal cell lines and animal models, including rats, mice, zebrafish, and avian species. In this review, we comprehensively discuss the molecular mechanisms underlying 3-NPA-induced neurotoxicity and its relevance to HD. 3-NPA primarily exerts its effects by irreversibly inhibiting succinate dehydrogenase (SDH), leading to mitochondrial dysfunction and energy failure. This metabolic disruption triggers oxidative stress, excitotoxicity, calcium dysregulation, and neuroinflammation, ultimately leading to selective striatal neurodegeneration and HD-like behavioral abnormalities. In addition to central nervous system effects, we also summarize the peripheral toxicities associated with 3-NPA, including skeletal muscle wasting, renal and hepatic dysfunction, ovarian stress, and cardiotoxicity. While 3-NPA effectively recapitulates several key pathological features of HD, it does not reproduce mutant huntingtin aggregation or progressive disease progression, representing a major limitation of this model. Overall, 3-NPA-induced pathology serves as a valuable experimental tool for studying specific aspects of HD, particularly mitochondrial dysfunction and related downstream pathways. Future studies integrating metabolic and genetic models will be essential to achieve a more comprehensive understanding of HD pathogenesis and to facilitate the development of effective therapeutic strategies.