Huntington's Disease Pathogenesis and Therapeutic Approaches

Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder caused by expansion of a CAG trinucleotide repeat in the huntingtin gene, leading to a mutant huntingtin protein with an extended polyglutamine tract. Although huntingtin is expressed throughout the body, neurons of the striatum—particularly medium spiny neurons—are especially vulnerable. Pathogenic mechanisms include misfolding and aggregation of mutant huntingtin, disruption of transcriptional regulation, impaired mitochondrial function, altered proteostasis and a chronic neuroinflammatory response. Somatic expansion of the CAG repeat in affected neurons amplifies toxicity over time, precipitating selective synaptic loss, dendritic retraction and eventual neuronal death. Therapeutic strategies aim to slow or halt these processes at multiple levels. Gene-lowering approaches, including antisense oligonucleotides and RNA interference, seek to reduce mutant huntingtin production. Small molecules are in development to stabilise protein folding, enhance clearance of aggregates or modulate DNA-repair pathways to curb repeat expansion. Immune-modulating agents target microglial activation and complement-mediated synapse elimination. In parallel, efforts to identify reliable biomarkers of disease progression have accelerated, facilitating earlier intervention and more efficient clinical trial design. Taken together, these advances point toward a future in which combination therapies may delay onset, preserve function and improve quality of life for individuals at risk of or living with HD.

Research from Nature Portfolio

Recent studies have demonstrated that activation of the complement cascade contributes directly to early corticostriatal synapse loss. In preclinical models, blocking C1q or disrupting microglial complement receptors prevented synaptic elimination, restored excitatory input to the striatum and rescued early cognitive deficits. Deep molecular profiling of human striatal and cerebellar nuclei has revealed cell-type-specific patterns of CAG repeat instability, implicating DNA mismatch-repair factors MSH2 and MSH3 in driving somatic expansion within medium spiny neurons and interneurons. These data support a model in which expansion is necessary, though not solely sufficient, for neuronal dysfunction. Work on RNA processing has uncovered mislocalisation and phosphorylation of the splicing regulator TDP-43 in HD, coupled with reductions in m6A RNA modification at transcripts involved in synaptic and metabolic pathways. Loss of TDP-43 function and altered m6A methylation combine to drive aberrant exon skipping, linking RNA-processing defects to early pathogenesis and identifying new molecular targets for intervention.

Huntington's Disease Pathogenesis and Therapeutic Approaches publication trend

The graph below shows the total number of articles in huntington's disease pathogenesis and therapeutic approaches across all publications each year (not limited to Nature Index journals).

Technical terms

CAG repeat expansion: An abnormal increase in the number of cytosine-adenine-guanine trinucleotide repeats in the huntingtin gene that underlies HD pathogenesis.

Somatic expansion: Progressive lengthening of the CAG repeat within individual cells over a lifetime, exacerbating mutant huntingtin toxicity.

Complement cascade: A series of innate immune proteins that tag synapses for removal by microglia, contributing to early synaptic loss.

Microglia: Resident immune cells of the central nervous system that mediate synaptic pruning and neuroinflammation in HD.

Antisense oligonucleotide: A short strand of modified nucleic acid designed to bind huntingtin mRNA and reduce production of mutant protein.

Neurofilament light protein (NfL): A structural axonal protein detectable in blood, serving as a marker of neuronal damage and disease progression.

References

1. Microglia and complement mediate early corticostriatal synapse loss and cognitive dysfunction in Huntington’s disease. Nature Medicine (2023).
2. Cell-type-specific CAG repeat expansions and toxicity of mutant Huntingtin in human striatum and cerebellum. Nature Genetics (2024).
3. Aberrant splicing in Huntington’s disease accompanies disrupted TDP-43 activity and altered m6A RNA modification. Nature Neuroscience (2025).
4. Long somatic DNA-repeat expansion drives neurodegeneration in Huntington’s disease. Cell (2025).
5. Neurofilament light protein in blood as a potential biomarker of neurodegeneration in Huntington's disease: a retrospective cohort analysis. The Lancet Neurology (2017).
6. Huntington's disease: a clinical review. European Journal of Neurology (2017).