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<p>Tay-Sachs disease (TSD) is a fatal lysosomal storage disorder caused by mutations in the <i>HEXA</i> gene which impair B-hexosaminidase A activity and result in the toxic accumulation of GM2 gangliosides. Here, we report the generation of a novel mouse model that harbors a partially humanized <i>Hexa</i> gene carrying c.1278insTATC, the most prevalent TSD-causing variant, and a <i>Neu3</i> deficiency to circumvent a murine bypass pathway. Upon characterization, this model reflects key pathological features of TSD including significant GM2 deposition in the central nervous system (CNS), prominent astrogliosis, neuroinflammation, and exhibit progressive neurobehavioral impairments. Retinal characterization revealed widespread GM2 accumulation leading to structural changes detectable by optical tomography coherence and fundus imaging, highlighting the significance of retinal involvement in TSD. Taken together, these findings establish this model as a valuable tool for elucidating TSD pathophysiology and provides a platform for evaluating targeted therapeutic strategies in a genetically accurate and clinically relevant context.</p>

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A novel humanized mouse model exhibits neurobehavioral impairments and recapitulates key neuropathological features of infantile Tay-Sachs disease

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年4月7日

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  • Lujaina Elbakr,
  • Georgiana Forguson,
  • Hong Anh Truong,
  • Joshua E. Hung,
  • Wing Suen Chan,
  • Dong-Kyu Kim,
  • Reid A. Brewer,
  • Sydney Steiman,
  • Toan Q. Nguyen,
  • Ajoy Vincent,
  • Evgueni A. Ivakine

摘要

Tay-Sachs disease (TSD) is a fatal lysosomal storage disorder caused by mutations in the HEXA gene which impair B-hexosaminidase A activity and result in the toxic accumulation of GM2 gangliosides. Here, we report the generation of a novel mouse model that harbors a partially humanized Hexa gene carrying c.1278insTATC, the most prevalent TSD-causing variant, and a Neu3 deficiency to circumvent a murine bypass pathway. Upon characterization, this model reflects key pathological features of TSD including significant GM2 deposition in the central nervous system (CNS), prominent astrogliosis, neuroinflammation, and exhibit progressive neurobehavioral impairments. Retinal characterization revealed widespread GM2 accumulation leading to structural changes detectable by optical tomography coherence and fundus imaging, highlighting the significance of retinal involvement in TSD. Taken together, these findings establish this model as a valuable tool for elucidating TSD pathophysiology and provides a platform for evaluating targeted therapeutic strategies in a genetically accurate and clinically relevant context.