ArticleHuman molecular genetics2014
Reversibility of neuropathology in Tay-Sachs-related diseases.
Article in Human molecular genetics, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 35 papers.
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Who cites it
35 citing papers in PubMed, 58 citations in OpenAlex.
- Modeling Tay-Sachs Disease in Astrocyte-like Cells Reveals Significant Changes in the Transcriptomic Profile.International journal of molecular sciences · 2026Article
- AAV-based gene therapy with modified HEXB confers lasting therapeutic benefits in GM2 gangliosidosis models.Cell reports. Medicine · 2026Article
- Sphingolipidoses: expanding the spectrum of α-synucleinopathies.Journal of neural transmission (Vienna, Austria : 1996) · 2026Review
- Sinbaglustat is efficacious in GM2 gangliosidosis primarily through inhibition of GBA2 rather than GCS.Molecular therapy. Advances · 2026Article
- The Role of Oligodendrocytes in Neurodegenerative Diseases: Unwrapping the Layers.International journal of molecular sciences · 2025Review
- Fucosidosis: A Review of a Rare Disease.International journal of molecular sciences · 2025Review
- Intracerebroventricular administration of a modified hexosaminidase ameliorates late-stage neurodegeneration in a GM2 mouse model.PloS one · 2025Article
- Treating late-onset Tay Sachs disease: Brain delivery with a dual trojan horse protein.Molecular therapy. Methods & clinical development · 2024Article
- Review
- Therapeutic advantages of combined gene/cell therapy strategies in a murine model of GM2 gangliosidosis.Molecular therapy. Methods & clinical development · 2022Article
- Glycosphingolipid metabolism and its role in ageing and Parkinson's disease.Glycoconjugate journal · 2022Review
- Therapeutic benefit after intracranial gene therapy delivered during the symptomatic stage in a feline model of Sandhoff disease.Gene therapy · 2021Article
- Lipids, lysosomes and mitochondria: insights into Lewy body formation from rare monogenic disorders.Acta neuropathologica · 2021Review
- GM1 Gangliosidosis: Mechanisms and Management.The application of clinical genetics · 2021Review
- White Matter Pathology as a Barrier to Gangliosidosis Gene Therapy.Frontiers in cellular neuroscience · 2021Review
- Decrease in Myelin-Associated Lipids Precedes Neuronal Loss and Glial Activation in the CNS of the Sandhoff Mouse as Determined by Metabolomics.Metabolites · 2020Article
- Pronounced Therapeutic Benefit of a Single Bidirectional AAV Vector Administered Systemically in Sandhoff Mice.Molecular therapy : the journal of the American Society of Gene Therapy · 2020Article
- Upregulating β-hexosaminidase activity in rodents prevents α-synuclein lipid associations and protects dopaminergic neurons from α-synuclein-mediated neurotoxicity.Acta neuropathologica communications · 2020Article
- Ngly1 -/- rats develop neurodegenerative phenotypes and pathological abnormalities in their peripheral and central nervous systems.Human molecular genetics · 2020Article
- Pre-clinical Mouse Models of Neurodegenerative Lysosomal Storage Diseases.Frontiers in molecular biosciences · 2020Review
Corrections and comments
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Authors and funding
5 authors at 2 institutions in 2 countries.
Funding
Abstract
The GM2 gangliosidoses are progressive neurodegenerative disorders due to defects in the lysosomal β-N-acetylhexosaminidase system. Accumulation of β-hexosaminidases A and B substrates is presumed to cause this fatal condition. An authentic mouse model of Sandhoff disease (SD) with pathological characteristics resembling those noted in infantile GM2 gangliosidosis has been described. We have shown that expression of β-hexosaminidase by intracranial delivery of recombinant adeno-associated viral vectors to young adult SD mice can prevent many features of the disease and extends lifespan. To investigate the nature of the neurological injury in GM2 gangliosidosis and the extent of its reversibility, we have examined the evolution of disease in the SD mouse; we have moreover explored the effects of gene transfer delivered at key times during the course of the illness. Here we report greatly increased survival only when the therapeutic genes are expressed either before the disease is apparent or during its early manifestations. However, irrespective of when treatment was administered, widespread and abundant expression of β-hexosaminidase with consequent clearance of glycoconjugates, α-synuclein and ubiquitinated proteins, and abrogation of inflammatory responses and neuronal loss was observed. We also show that defects in myelination occur in early life and cannot be easily resolved when treatment is given to the adult brain. These results indicate that there is a limited temporal opportunity in which function and survival can be improved-but regardless of resolution of the cardinal pathological features of GM2 gangliosidosis, a point is reached when functional deterioration and death cannot be prevented.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.