HTT (huntingtin)
HTT is the gene that causes Huntington’s disease, making it one of the clearest examples in all of neurodegeneration where a single genetic change leads directly to disease. It follows an autosomal dominant inheritance pattern, meaning that inheriting one mutated copy is sufficient to eventually develop the condition. Because the cause is so well-defined, it provides a model for understanding how a specific molecular defect can lead to progressive dysfunction across entire brain networks.
Normal function
HTT encodes the huntingtin protein, which is widely expressed throughout the body and importantly in the brain. While its full range of functions is still being defined, huntingtin is involved in intracellular transport, vesicle trafficking (the movement of molecules between compartments of the cell), gene expression regulation, and neuronal survival. In neurons, huntingtin helps support long-distance transport along axons, which is critical for maintaining function in the synapse. It also appears to play a role in protecting cells from stress and supporting normal development. This means that the protein is not just present, but actively important for neuronal health.
Mutation and effect
Huntington’s disease is caused by an expansion of a CAG repeat sequence within the HTT gene. This leads to an abnormally long stretch of glutamines in the huntingtin protein, often referred to as a polyglutamine (polyQ) expansion. This mutation causes two major problems: the protein becomes prone to misfolding and aggregation and the protein’s normal functions are disrupted. The number of repeats strongly influences disease onset. Larger expansions typically lead to earlier onset, a phenomenon known as anticipation, where the disease appears earlier in successive generations. Over time, the number of repeats will increase in a patient.
Implications for treatment
Huntington’s disease is characterized by progressive degeneration of neurons, especially in the striatum and connected brain regions. This leads to movement abnormalities (chorea), cognitive decline, and psychiatric symptoms. Compared with other neurodegenerative diseases, Huntington’s has a more predictable progression once symptoms begin. One notable feature is that pathology begins years before clinical symptoms. HTT is one of the most important targets in neurodegenerative therapy because the disease is driven by a single toxic protein. This has led to strong interest in lowering mutant huntingtin levels. Approaches include Antisense oligonucleotides (ASOs) to reduce HTT expression, RNA-targeting therapies, and gene-editing strategies (read more about these here!). While early clinical trials have had mixed results, the overall strategy remains one of the most promising in the field. Huntington’s disease is often viewed as a test case for gene-targeted therapies in neurodegeneration.
Research focus
Research is focused on determining how much huntingtin reduction is needed to be beneficial and how early treatment must begin. There is also interest in understanding how different mechanisms like aggregation, transcriptional changes, mitochondrial dysfunction, and transport defects interact to drive disease. Because individuals can be identified genetically before symptoms appear, Huntington’s disease is a major focus of pre-symptomatic intervention trials, which aim to delay or prevent disease onset. More broadly, HTT research is helping define how gene-targeted therapies might be applied to other neurodegenerative diseases.
Sources
- Saudou, F., & Humbert, S. (2016). The Biology of Huntingtin.
- Mätlik, K., et al. (2024). Cell-type-specific CAG repeat expansions and toxicity of mutant huntingtin in human striatum and cerebellum.
- Snell, R. G., MacMillan, J. C., Cheadle, J. P., et al. (1993). Relationship between trinucleotide repeat expansion and phenotypic variation in Huntington’s disease.