Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by an expanded CAG trinucleotide repeat in the HTT gene, which encodes the huntingtin protein. The pathogenic expansion results in a mutant huntingtin protein (mHTT) with an expanded polyglutamine (polyQ) tract that gains toxic functions while losing normal protective activities. This page outlines the key molecular and cellular mechanisms driving HD pathogenesis.
| Property | Value |
|---|---|
| Causative Gene | HTT (Huntingtin) |
| Mutation | CAG trinucleotide repeat expansion |
| Normal CAG Repeats | ≤26 |
| Pathogenic CAG Repeats | ≥36 |
| Protein Product | Huntingtin protein (3,144 amino acids) |
| Primary Brain Regions Affected | Striatum (caudate, putamen), cerebral cortex |
| Key Pathological Features | mHTT aggregates, striatal neuron loss, cortical atrophy |
The expanded polyglutamine tract in mutant huntingtin (mHTT) leads to toxic gain-of-function through multiple interconnected mechanisms:
Protein Misfolding and Aggregation
Loss of Normal Huntingtin Function
Mutant huntingtin disrupts gene expression through multiple mechanisms:
Transcription Factor Sequestration
DNA Damage and Repair
Gene Expression Changes
Mitochondrial impairment is a central feature of HD pathogenesis:
Energy Metabolism Defects
PGC-1α Dysregulation
Mitochondrial Dynamics
Calcium Handling
The striatum, particularly medium spiny neurons (MSNs), shows the earliest and most severe degeneration in HD:
Progressive cortical degeneration accompanies striatal loss:
Microglial activation is prominent throughout HD progression:
Recent genetic studies have identified modifiers of HD onset and progression:
| Gene | Modifier Effect | Reference |
|---|---|---|
| MSH3 | Modifies age at onset; DNA mismatch repair | [7] |
| FAN1 | DNA repair nuclease; onset modifier | |
| RHA | Repeat-binding protein | |
| RAN | Translation of Repeat-Containing Proteins |
| Target | Approach | Development Status |
|---|---|---|
| HTT Gene | ASO gene silencing (Tominersen) | Phase 3 (GENERATION-HD2) |
| HTT Gene | AAV RNAi delivery | Preclinical |
| Mutant Protein | Aggregation inhibitors | Research |
| Transcriptional dysfunction | HDAC inhibitors | Phase 2 |
| Mitochondrial function | PGC-1α activators | Research |
| Neuroinflammation | Microglial modulation | Research |
| BDNF signaling | BDNF mimetics | Research |
Saudou F, Humbert S. The Biology of Huntingtin. Neuron. 2016. ↩︎
Lands C, et al. Huntington's disease: underlying molecular mechanisms. Acta Neuropathol. 2012. ↩︎
Hunt CA, et al. Transcriptional dysregulation in Huntington's disease. Trends Neurosci. 2011. ↩︎
Gu M, et al. Mitochondrial dysfunction in Huntington's disease. J Clin Invest. 2011. ↩︎
Kim J, et al. Impaired mitochondrial function in Huntington's disease. Nat Rev Neurol. 2010. ↩︎
Taylor JP, et al. Neuroinflammation in Huntington's disease. Nat Rev Neurol. 2016. ↩︎ ↩︎
Sportelli C, et al. Genetic modifiers of Huntington's disease. J Huntington Dis. 2020. ↩︎