| Huntingtin (HTT) | |
|---|---|
| Gene | HTT |
| UniProt | P42857 |
| Mol. Weight | ~350 kDa (full-length) |
| Localization | Cytosol, nucleus, synapses |
| Family | HTT family, HEAT repeat proteins |
| Diseases | Huntington's Disease |
Huntingtin (HTT) is a large (~350 kDa) protein encoded by the HTT gene on chromosome 4p16.3. While the normal function of Huntingtin remains incompletely understood, it is essential for embryonic development and neuronal health. The discovery that CAG repeat expansions in HTT cause Huntington's disease established it as the causative gene for this devastating autosomal dominant neurodegenerative disorder. Mutant Huntingtin (mHTT) with expanded polyglutamine (polyQ) tracts acquires toxic properties that lead to progressive striatal and cortical degeneration. Huntington's disease affects approximately 1 in 10,000 people worldwide, with typical onset in middle age and progressive motor, cognitive, and psychiatric symptoms leading to death within 15-20 years of onset.
Huntingtin (HTT) is a large (~350 kDa) protein encoded by the HTT gene on chromosome 4p16.3. While the normal function of Huntingtin remains incompletely understood, it is essential for embryonic development and neuronal health. The discovery that CAG repeat expansions in HTT cause Huntington's disease established it as the causative gene for this devastating autosomal dominant neurodegenerative disorder. Mutant Huntingtin (mHTT) with expanded polyglutamine (polyQ) tracts acquires toxic properties that lead to progressive striatal and cortical degeneration.
HTT is one of the largest proteins in the human proteome with 3,144 amino acids. Its HEAT repeat domain mediates numerous protein-protein interactions:
Wild-type HTT is essential for development and neuronal survival:
The CAG repeat expansion in HTT results in an expanded polyglutamine (polyQ) tract in the N-terminal region of the protein. The age of onset correlates inversely with repeat length—longer repeats cause earlier onset. The polyQ expansion causes:
Conformational change: The expanded polyQ promotes abnormal protein folding and aggregation
Proteolytic cleavage: mHTT is more susceptible to proteolytic cleavage, generating toxic N-terminal fragments
Loss of normal function: The mutation may disrupt normal HTT interactions with cellular proteins
Mutant HTT acquires novel toxic properties:
Aggregation: mHTT forms insoluble aggregates in neurons, disrupting cellular function
Transcriptional dysregulation: mHTT alters gene expression patterns, particularly in striatal medium spiny neurons
Mitochondrial dysfunction: mHTT impairs mitochondrial trafficking, function, and dynamics
Axonal transport defects: mHTT disrupts vesicle and organelle transport along axons
Synaptic dysfunction: mHTT alters neurotransmitter release and synaptic plasticity
Autophagy impairment: mHTT impairs autophagic clearance of cellular debris
Striatal medium spiny neurons (MSNs) and cortical neurons are particularly vulnerable in HD. This selective vulnerability involves:
ASO therapy: Antisense oligonucleotides designed to reduce mHTT expression have shown promise in clinical trials. Tominersen (RG6042) was evaluated in the Phase 3 GENERATION HD1 trial.
Gene therapy: Viral vectors delivering RNAi or CRISPR-based approaches to silence mutant HTT
Protein clearing: Small molecules that enhance autophagy or proteasome-mediated clearance of mHTT aggregates
Aggregation inhibitors: Compounds that prevent mHTT aggregation or promote aggregate dissolution
The study of Huntingtin (Htt) has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.
Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.