Tay-Sachs disease (TSD) is a neurodegenerative disorder caused by mutations in the HEXA gene, encoding the α-subunit of β-hexosaminidase A. HexA deficiency leads to impaired degradation and accumulation of GM2 ganglioside, causing progressive neurodegeneration in patients. Interestingly, Hexa−/− mice show a relatively mild phenotype, suggesting degradation of stored GM2 ganglioside through a ‘bypass’ involving a sialidase. To investigate whether sialidase Neu3 contributes to GM2 degradation, mice deficient in both HEXA and NEU3 , Hexa−/−Neu3−/− , were generated. Abnormal GM2 accumulation was revealed in the brains of Hexa−/−Neu3−/− mice using thin-layer chromatography and mass spectrometric analyses. Immunohistological and histological analyses indicated astrogliosis, Purkinje cell loss, and progressive neurodegeneration. Furthermore, the mice exhibited marked neurological abnormalities, including slowed movement, ataxia, and tremors, as well as a shortened lifespan of approximately 20 weeks. Hence, Hexa−/−Neu3−/− mice, which mimic the neuropathological and clinical abnormalities observed in patients, were considered the early-onset TSD model. The role of endogenous human Neu3 in GM2 degradation remains unknown. To evaluate its therapeutic potential, we administered AAVrh10-hNeu3 intrathecally to 8-week-old Hexa−/−Neu3−/− mice, either alone or with an anti-inflammatory agent, Istradefylline. Treatment with human Neu3 and Istradefylline extended lifespan to 28 weeks, improved body weight, and reduced GM2 accumulation. Additionally, fewer lysosomal LAMP1- and TUNEL-positive cells, and higher CNPase levels were revealed. Rotarod and footprint analyses showed improvements at 20 weeks. Our results provide the first in vivo evidence that AAV-mediated human Neu3 expression and Istradefylline may slow disease progression, reduce neuropathology, and lessen motor deficits in the Hexa−/−Neu3−/− mouse model of TSD. • AAVrh10-hNeu3 administration extended the lifespan of DKO mice from 20 to 28 weeks. • AAVrh10-hNeu3 gene therapy partially reduced GM2 ganglioside accumulation, especially at 20 weeks. • Combined AAV and ISD therapy further enhanced neuronal survival and decreased TUNEL-positive cells. • Co-administration of AAV and ISD modulated lysosomal and inflammatory responses in DKO mouse brains. • Human Neu3 expression slowed disease progression but did not completely prevent late-stage pathology.
Basırlı et al. (Tue,) studied this question.