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

Authors

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

Published in

Journal of neuroinflammation. Volume 23. Issue 1. Apr 07, 2026. Epub Apr 07, 2026.

Abstract

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.
The online version contains supplementary material available at 10.1186/s12974-026-03783-6.

PMID:
41947150
Bibliographic data and abstract were imported from PubMed on 15 Jun 2026.

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