Version history

{
  "content_md": "# Huntingtin Protein\n\n## Overview\n\n\n```mermaid\nflowchart TD\n    HUNTINGTIN_PROTEIN[\"HUNTINGTIN_PROTEIN\"]\n    HUNTINGTIN_PROTEIN_1[\"table\"]\n    HUNTINGTIN_PROTEIN -->|\"related to\"| HUNTINGTIN_PROTEIN_1\n    style HUNTINGTIN_PROTEIN_1 fill:#81c784,stroke:#333,color:#000\n    HUNTINGTIN_PROTEIN_2[\"class\"]\n    HUNTINGTIN_PROTEIN -->|\"related to\"| HUNTINGTIN_PROTEIN_2\n    style HUNTINGTIN_PROTEIN_2 fill:#81c784,stroke:#333,color:#000\n    HUNTINGTIN_PROTEIN_3[\"infobox\"]\n    HUNTINGTIN_PROTEIN -->|\"related to\"| HUNTINGTIN_PROTEIN_3\n    style HUNTINGTIN_PROTEIN_3 fill:#81c784,stroke:#333,color:#000\n    style HUNTINGTIN_PROTEIN fill:#4fc3f7,stroke:#333,color:#000\n```\n\n<table class=\"infobox infobox-protein\">\n  <tr>\n    <th class=\"infobox-header\" colspan=\"2\">Huntingtin Protein</th>\n  </tr>\n  <tr>\n    <td class=\"label\">Agent</td>\n    <td>Target</td>\n  </tr>\n  <tr>\n    <td class=\"label\">Tominersen</td>\n    <td>HTT ASO</td>\n  </tr>\n  <tr>\n    <td class=\"label\">ASO-HTTRx</td>\n    <td>HTT</td>\n  </tr>\n  <tr>\n    <td class=\"label\">others</td>\n    <td>Various</td>\n  </tr>\n  <tr>\n    <td class=\"label\">Partner</td>\n    <td>Interaction Type</td>\n  </tr>\n  <tr>\n    <td class=\"label\">HAP40</td>\n    <td>Protein binding</td>\n  </tr>\n  <tr>\n    <td class=\"label\">BDNF</td>\n    <td>Transcriptional regulation</td>\n  </tr>\n  <tr>\n    <td class=\"label\">CBP/p300</td>\n    <td>Transcription</td>\n  </tr>\n  <tr>\n    <td class=\"label\">RAB11</td>\n    <td>Vesicle transport</td>\n  </tr>\n  <tr>\n    <td class=\"label\">p53</td>\n    <td>[Apoptosis](/entities/apoptosis) regulation</td>\n  </tr>\n</table>\n\n**[Huntingtin Protein](/proteins/huntingtin)** is a protein that huntingtin is essential for embryonic development and has multiple functions in the adult nervous system[1]:. This page describes its structure, normal nervous system function, role in neurodegenerative disease, and potential as a therapeutic target. [@huntingtin2020]\n\n## Structure\n\nHuntingtin (HTT) is one of the largest known proteins, with 3,144 amino acids in the canonical isoform. It is characterized by several structural features[1]:\n\n### Domain Architecture\n\n- **N-terminal domain (1-90 aa)**: Contains the polyglutamine (polyQ) tract (CAG repeat, normally 10-35)\n- **HEAT repeat domain (90-1,700 aa)**: ~23 HEAT repeats; mediates protein-protein interactions\n- **Bridge region (1,700-2,200 aa)**: Flexible linker with multiple proline-rich motifs\n- **C-terminal domain (2,200-3,144 aa)**: Contains additional HEAT repeats and regulatory sequences\n\nThe HEAT repeats form alpha-helical solenoids that mediate interactions with numerous partner proteins. The polyQ tract length determines pathogenicity—expansion beyond ~36 repeats causes Huntington's disease[1].\n\n### Post-Translational Modifications\n\n- **Phosphorylation**: At Ser-16, Ser-421, Thr-47 (neuroprotective)\n- **Acetylation**: At Lys-44, Lys-555 (affects aggregation and clearance)\n- **Sumoylation**: Multiple sites\n- **Palmitoylation**: At Cys-214 (membrane association)\n- **Proteolytic cleavage**: By caspases, calpains generating toxic N-terminal fragments\n\n## Normal Function\n\nHuntingtin is essential for embryonic development and has multiple functions in the adult nervous system[1]:\n\n### Vesicle Trafficking\n\n- **Axonal transport**: Associates with dynein/dynactin and kinesin for vesicle movement\n- **Synaptic vesicle function**: Regulates neurotransmitter release\n- **Endocytic pathway**: Involved in receptor trafficking\n\n### Gene Expression Regulation\n\n- **Transcriptional co-activator**: Interacts with p53, [NF-κB](/entities/nf-kb), and other transcription factors\n- **Chromatin remodeling**: Associates with histone acetyltransferases (CBP, p300)\n- **BDNF transcription**: Positively regulates BDNF expression\n\n### Cellular Protection\n\n- **Anti-apoptotic function**: Sequesters pro-apoptotic proteins\n- **Mitochondrial function**: Supports mitochondrial dynamics and quality\n- **[Autophagy](/entities/autophagy) regulation**: Involved in selective autophagy\n\n### Developmental Functions\n\n- **Early development**: Essential for gastrulation\n- **Neuronal survival**: Supports cortical and striatal neuron viability\n- **Synapse formation**: Regulates dendritic spine development\n\n## Role in Neurodegeneration\n\n### Huntington's Disease (HD)\n\n**CAG repeat expansion** (≥36 repeats) causes autosomal dominant Huntington's disease[1]:\n\n#### Pathogenic Mechanisms\n\n- **Toxic gain of function**: Mutant HTT forms aggregates in [neurons](/entities/neurons)[2]\n- **Loss of normal function**: Disrupted protein interactions[2]\n- **Transcriptional dysregulation**: Altered gene expression patterns[2]\n- **Mitochondrial dysfunction**: Energy deficit and oxidative stress[2]\n- **Axonal transport defects**: Impaired vesicle trafficking\n\n#### Neuropathology\n\n- **Striatal degeneration**: Medium spiny neurons particularly vulnerable\n- **Cortical atrophy**: Progressive loss of cortical volume\n- **HTT inclusions**: Mutant protein aggregates throughout brain\n- **White matter changes**: Demyelination and axonal loss\n\n#### Systemic Features\n\n- **Peripheral manifestations**: Muscle wasting, metabolic changes\n- **Cognitive decline**: Executive dysfunction, eventually dementia\n- **Psychiatric symptoms**: Depression, anxiety, psychosis\n\n### Role in Other Neurodegenerative Diseases\n\n- **Alzheimer's disease**: HTT may interact with [APP](/entities/app-protein) and [tau](/proteins/tau)\n- **Parkinson's disease**: Altered autophagy in PD linked to HTT\n- **ALS**: HTT inclusions in some ALS cases\n\n### Mechanisms of Toxicity\n\n1. **Aggregate formation**: Toxic oligomers and inclusions\n2. **Transcriptional dysregulation**: Sequestration of transcriptional co-activators\n3. **Mitochondrial dysfunction**: Impaired energy metabolism\n4. **Axonal transport disruption**: Loss of neurotrophic support\n5. **Synaptic failure**: Impaired neurotransmitter release\n\n## Therapeutic Targeting\n\n### Gene Silencing Approaches\n\n- **Antisense oligonucleotides (ASOs)**: Multiple clinical trials (e.g., Tominersen, others)\n- **RNAi and CRISPR**: Under development\n- **Allele-specific targeting**: Targeting mutant allele specifically\n\n### Protein-Targeting Strategies\n\n- **Aggregation inhibitors**: Small molecules to prevent aggregation\n- **HTT phosphorylation**: Modulating protective phosphorylation sites\n- **Proteostasis enhancement**: Autophagy inducers\n\n### Symptomatic Treatments\n\n- **Motor symptoms**: Tetrabenazine, VMAT2 inhibitor\n- **Cognitive dysfunction**: Under investigation\n- **Psychiatric symptoms**: Standard treatments\n\n### Disease Modification\n\n- **Neuroprotective strategies**: BDNF enhancement, mitochondrial protectants\n- **Cell replacement therapy**: Stem cell approaches under investigation\n- **Gene therapy**: AAV-delivered gene silencing\n\n### Clinical Trials\n\n## Protein Interactions\n\n## See Also\n\n- [Alzheimer's Disease](/diseases/alzheimers-disease)\n- [Parkinson's Disease](/diseases/parkinsons-disease)\n\n## External Links\n\n- [PubMed](https://pubmed.ncbi.nlm.nih.gov/)\n- [KEGG Pathways](https://www.genome.jp/kegg/pathway.html)\n\n## References\n\n1. [Unknown, Huntingtin structure and function (Cell 2020) (2020)](https://doi.org/10.1016/j.cell.2020.06.025)\n2. [Unknown, Huntington's disease pathogenesis (Nat Rev Neurosci 2021) (2021)](https://doi.org/10.1038/s41583-021-00478-0)",
  "entity_type": "protein"
}

{
  "content_md": "# Huntingtin Protein\n\n## Overview\n\n<table class=\"infobox infobox-protein\">\n  <tr>\n    <th class=\"infobox-header\" colspan=\"2\">Huntingtin Protein</th>\n  </tr>\n  <tr>\n    <td class=\"label\">Agent</td>\n    <td>Target</td>\n  </tr>\n  <tr>\n    <td class=\"label\">Tominersen</td>\n    <td>HTT ASO</td>\n  </tr>\n  <tr>\n    <td class=\"label\">ASO-HTTRx</td>\n    <td>HTT</td>\n  </tr>\n  <tr>\n    <td class=\"label\">others</td>\n    <td>Various</td>\n  </tr>\n  <tr>\n    <td class=\"label\">Partner</td>\n    <td>Interaction Type</td>\n  </tr>\n  <tr>\n    <td class=\"label\">HAP40</td>\n    <td>Protein binding</td>\n  </tr>\n  <tr>\n    <td class=\"label\">BDNF</td>\n    <td>Transcriptional regulation</td>\n  </tr>\n  <tr>\n    <td class=\"label\">CBP/p300</td>\n    <td>Transcription</td>\n  </tr>\n  <tr>\n    <td class=\"label\">RAB11</td>\n    <td>Vesicle transport</td>\n  </tr>\n  <tr>\n    <td class=\"label\">p53</td>\n    <td>[Apoptosis](/entities/apoptosis) regulation</td>\n  </tr>\n</table>\n\n**[Huntingtin Protein](/proteins/huntingtin)** is a protein that huntingtin is essential for embryonic development and has multiple functions in the adult nervous system[1]:. This page describes its structure, normal nervous system function, role in neurodegenerative disease, and potential as a therapeutic target. [@huntingtin2020]\n\n## Structure\n\nHuntingtin (HTT) is one of the largest known proteins, with 3,144 amino acids in the canonical isoform. It is characterized by several structural features[1]:\n\n### Domain Architecture\n\n- **N-terminal domain (1-90 aa)**: Contains the polyglutamine (polyQ) tract (CAG repeat, normally 10-35)\n- **HEAT repeat domain (90-1,700 aa)**: ~23 HEAT repeats; mediates protein-protein interactions\n- **Bridge region (1,700-2,200 aa)**: Flexible linker with multiple proline-rich motifs\n- **C-terminal domain (2,200-3,144 aa)**: Contains additional HEAT repeats and regulatory sequences\n\nThe HEAT repeats form alpha-helical solenoids that mediate interactions with numerous partner proteins. The polyQ tract length determines pathogenicity—expansion beyond ~36 repeats causes Huntington's disease[1].\n\n### Post-Translational Modifications\n\n- **Phosphorylation**: At Ser-16, Ser-421, Thr-47 (neuroprotective)\n- **Acetylation**: At Lys-44, Lys-555 (affects aggregation and clearance)\n- **Sumoylation**: Multiple sites\n- **Palmitoylation**: At Cys-214 (membrane association)\n- **Proteolytic cleavage**: By caspases, calpains generating toxic N-terminal fragments\n\n## Normal Function\n\nHuntingtin is essential for embryonic development and has multiple functions in the adult nervous system[1]:\n\n### Vesicle Trafficking\n\n- **Axonal transport**: Associates with dynein/dynactin and kinesin for vesicle movement\n- **Synaptic vesicle function**: Regulates neurotransmitter release\n- **Endocytic pathway**: Involved in receptor trafficking\n\n### Gene Expression Regulation\n\n- **Transcriptional co-activator**: Interacts with p53, [NF-κB](/entities/nf-kb), and other transcription factors\n- **Chromatin remodeling**: Associates with histone acetyltransferases (CBP, p300)\n- **BDNF transcription**: Positively regulates BDNF expression\n\n### Cellular Protection\n\n- **Anti-apoptotic function**: Sequesters pro-apoptotic proteins\n- **Mitochondrial function**: Supports mitochondrial dynamics and quality\n- **[Autophagy](/entities/autophagy) regulation**: Involved in selective autophagy\n\n### Developmental Functions\n\n- **Early development**: Essential for gastrulation\n- **Neuronal survival**: Supports cortical and striatal neuron viability\n- **Synapse formation**: Regulates dendritic spine development\n\n## Role in Neurodegeneration\n\n### Huntington's Disease (HD)\n\n**CAG repeat expansion** (≥36 repeats) causes autosomal dominant Huntington's disease[1]:\n\n#### Pathogenic Mechanisms\n\n- **Toxic gain of function**: Mutant HTT forms aggregates in [neurons](/entities/neurons)[2]\n- **Loss of normal function**: Disrupted protein interactions[2]\n- **Transcriptional dysregulation**: Altered gene expression patterns[2]\n- **Mitochondrial dysfunction**: Energy deficit and oxidative stress[2]\n- **Axonal transport defects**: Impaired vesicle trafficking\n\n#### Neuropathology\n\n- **Striatal degeneration**: Medium spiny neurons particularly vulnerable\n- **Cortical atrophy**: Progressive loss of cortical volume\n- **HTT inclusions**: Mutant protein aggregates throughout brain\n- **White matter changes**: Demyelination and axonal loss\n\n#### Systemic Features\n\n- **Peripheral manifestations**: Muscle wasting, metabolic changes\n- **Cognitive decline**: Executive dysfunction, eventually dementia\n- **Psychiatric symptoms**: Depression, anxiety, psychosis\n\n### Role in Other Neurodegenerative Diseases\n\n- **Alzheimer's disease**: HTT may interact with [APP](/entities/app-protein) and [tau](/proteins/tau)\n- **Parkinson's disease**: Altered autophagy in PD linked to HTT\n- **ALS**: HTT inclusions in some ALS cases\n\n### Mechanisms of Toxicity\n\n1. **Aggregate formation**: Toxic oligomers and inclusions\n2. **Transcriptional dysregulation**: Sequestration of transcriptional co-activators\n3. **Mitochondrial dysfunction**: Impaired energy metabolism\n4. **Axonal transport disruption**: Loss of neurotrophic support\n5. **Synaptic failure**: Impaired neurotransmitter release\n\n## Therapeutic Targeting\n\n### Gene Silencing Approaches\n\n- **Antisense oligonucleotides (ASOs)**: Multiple clinical trials (e.g., Tominersen, others)\n- **RNAi and CRISPR**: Under development\n- **Allele-specific targeting**: Targeting mutant allele specifically\n\n### Protein-Targeting Strategies\n\n- **Aggregation inhibitors**: Small molecules to prevent aggregation\n- **HTT phosphorylation**: Modulating protective phosphorylation sites\n- **Proteostasis enhancement**: Autophagy inducers\n\n### Symptomatic Treatments\n\n- **Motor symptoms**: Tetrabenazine, VMAT2 inhibitor\n- **Cognitive dysfunction**: Under investigation\n- **Psychiatric symptoms**: Standard treatments\n\n### Disease Modification\n\n- **Neuroprotective strategies**: BDNF enhancement, mitochondrial protectants\n- **Cell replacement therapy**: Stem cell approaches under investigation\n- **Gene therapy**: AAV-delivered gene silencing\n\n### Clinical Trials\n\n## Protein Interactions\n\n## See Also\n\n- [Alzheimer's Disease](/diseases/alzheimers-disease)\n- [Parkinson's Disease](/diseases/parkinsons-disease)\n\n## External Links\n\n- [PubMed](https://pubmed.ncbi.nlm.nih.gov/)\n- [KEGG Pathways](https://www.genome.jp/kegg/pathway.html)\n\n## References\n\n1. [Unknown, Huntingtin structure and function (Cell 2020) (2020)](https://doi.org/10.1016/j.cell.2020.06.025)\n2. [Unknown, Huntington's disease pathogenesis (Nat Rev Neurosci 2021) (2021)](https://doi.org/10.1038/s41583-021-00478-0)",
  "entity_type": "protein"
}

{
  "content_md": "## Overview\n\n<table class=\"infobox infobox-protein\">\n  <tr>\n    <th class=\"infobox-header\" colspan=\"2\">Huntingtin Protein</th>\n  </tr>\n  <tr>\n    <td class=\"label\">Agent</td>\n    <td>Target</td>\n  </tr>\n  <tr>\n    <td class=\"label\">Tominersen</td>\n    <td>HTT ASO</td>\n  </tr>\n  <tr>\n    <td class=\"label\">ASO-HTTRx</td>\n    <td>HTT</td>\n  </tr>\n  <tr>\n    <td class=\"label\">others</td>\n    <td>Various</td>\n  </tr>\n  <tr>\n    <td class=\"label\">Partner</td>\n    <td>Interaction Type</td>\n  </tr>\n  <tr>\n    <td class=\"label\">HAP40</td>\n    <td>Protein binding</td>\n  </tr>\n  <tr>\n    <td class=\"label\">BDNF</td>\n    <td>Transcriptional regulation</td>\n  </tr>\n  <tr>\n    <td class=\"label\">CBP/p300</td>\n    <td>Transcription</td>\n  </tr>\n  <tr>\n    <td class=\"label\">RAB11</td>\n    <td>Vesicle transport</td>\n  </tr>\n  <tr>\n    <td class=\"label\">p53</td>\n    <td>[Apoptosis](/entities/apoptosis) regulation</td>\n  </tr>\n</table>\n\n**[Huntingtin Protein](/proteins/huntingtin)** is a protein that huntingtin is essential for embryonic development and has multiple functions in the adult nervous system[1]:. This page describes its structure, normal nervous system function, role in neurodegenerative disease, and potential as a therapeutic target. [@huntingtin2020]\n\n## Structure\n\nHuntingtin (HTT) is one of the largest known proteins, with 3,144 amino acids in the canonical isoform. It is characterized by several structural features[1]:\n\n### Domain Architecture\n\n- **N-terminal domain (1-90 aa)**: Contains the polyglutamine (polyQ) tract (CAG repeat, normally 10-35)\n- **HEAT repeat domain (90-1,700 aa)**: ~23 HEAT repeats; mediates protein-protein interactions\n- **Bridge region (1,700-2,200 aa)**: Flexible linker with multiple proline-rich motifs\n- **C-terminal domain (2,200-3,144 aa)**: Contains additional HEAT repeats and regulatory sequences\n\nThe HEAT repeats form alpha-helical solenoids that mediate interactions with numerous partner proteins. The polyQ tract length determines pathogenicity—expansion beyond ~36 repeats causes Huntington's disease[1].\n\n### Post-Translational Modifications\n\n- **Phosphorylation**: At Ser-16, Ser-421, Thr-47 (neuroprotective)\n- **Acetylation**: At Lys-44, Lys-555 (affects aggregation and clearance)\n- **Sumoylation**: Multiple sites\n- **Palmitoylation**: At Cys-214 (membrane association)\n- **Proteolytic cleavage**: By caspases, calpains generating toxic N-terminal fragments\n\n## Normal Function\n\nHuntingtin is essential for embryonic development and has multiple functions in the adult nervous system[1]:\n\n### Vesicle Trafficking\n\n- **Axonal transport**: Associates with dynein/dynactin and kinesin for vesicle movement\n- **Synaptic vesicle function**: Regulates neurotransmitter release\n- **Endocytic pathway**: Involved in receptor trafficking\n\n### Gene Expression Regulation\n\n- **Transcriptional co-activator**: Interacts with p53, [NF-κB](/entities/nf-kb), and other transcription factors\n- **Chromatin remodeling**: Associates with histone acetyltransferases (CBP, p300)\n- **BDNF transcription**: Positively regulates BDNF expression\n\n### Cellular Protection\n\n- **Anti-apoptotic function**: Sequesters pro-apoptotic proteins\n- **Mitochondrial function**: Supports mitochondrial dynamics and quality\n- **[Autophagy](/entities/autophagy) regulation**: Involved in selective autophagy\n\n### Developmental Functions\n\n- **Early development**: Essential for gastrulation\n- **Neuronal survival**: Supports cortical and striatal neuron viability\n- **Synapse formation**: Regulates dendritic spine development\n\n## Role in Neurodegeneration\n\n### Huntington's Disease (HD)\n\n**CAG repeat expansion** (≥36 repeats) causes autosomal dominant Huntington's disease[1]:\n\n#### Pathogenic Mechanisms\n\n- **Toxic gain of function**: Mutant HTT forms aggregates in [neurons](/entities/neurons)[2]\n- **Loss of normal function**: Disrupted protein interactions[2]\n- **Transcriptional dysregulation**: Altered gene expression patterns[2]\n- **Mitochondrial dysfunction**: Energy deficit and oxidative stress[2]\n- **Axonal transport defects**: Impaired vesicle trafficking\n\n#### Neuropathology\n\n- **Striatal degeneration**: Medium spiny neurons particularly vulnerable\n- **Cortical atrophy**: Progressive loss of cortical volume\n- **HTT inclusions**: Mutant protein aggregates throughout brain\n- **White matter changes**: Demyelination and axonal loss\n\n#### Systemic Features\n\n- **Peripheral manifestations**: Muscle wasting, metabolic changes\n- **Cognitive decline**: Executive dysfunction, eventually dementia\n- **Psychiatric symptoms**: Depression, anxiety, psychosis\n\n### Role in Other Neurodegenerative Diseases\n\n- **Alzheimer's disease**: HTT may interact with [APP](/entities/app-protein) and [tau](/proteins/tau)\n- **Parkinson's disease**: Altered autophagy in PD linked to HTT\n- **ALS**: HTT inclusions in some ALS cases\n\n### Mechanisms of Toxicity\n\n1. **Aggregate formation**: Toxic oligomers and inclusions\n2. **Transcriptional dysregulation**: Sequestration of transcriptional co-activators\n3. **Mitochondrial dysfunction**: Impaired energy metabolism\n4. **Axonal transport disruption**: Loss of neurotrophic support\n5. **Synaptic failure**: Impaired neurotransmitter release\n\n## Therapeutic Targeting\n\n### Gene Silencing Approaches\n\n- **Antisense oligonucleotides (ASOs)**: Multiple clinical trials (e.g., Tominersen, others)\n- **RNAi and CRISPR**: Under development\n- **Allele-specific targeting**: Targeting mutant allele specifically\n\n### Protein-Targeting Strategies\n\n- **Aggregation inhibitors**: Small molecules to prevent aggregation\n- **HTT phosphorylation**: Modulating protective phosphorylation sites\n- **Proteostasis enhancement**: Autophagy inducers\n\n### Symptomatic Treatments\n\n- **Motor symptoms**: Tetrabenazine, VMAT2 inhibitor\n- **Cognitive dysfunction**: Under investigation\n- **Psychiatric symptoms**: Standard treatments\n\n### Disease Modification\n\n- **Neuroprotective strategies**: BDNF enhancement, mitochondrial protectants\n- **Cell replacement therapy**: Stem cell approaches under investigation\n- **Gene therapy**: AAV-delivered gene silencing\n\n### Clinical Trials\n\n## Protein Interactions\n\n## See Also\n\n- [Alzheimer's Disease](/diseases/alzheimers-disease)\n- [Parkinson's Disease](/diseases/parkinsons-disease)\n\n## External Links\n\n- [PubMed](https://pubmed.ncbi.nlm.nih.gov/)\n- [KEGG Pathways](https://www.genome.jp/kegg/pathway.html)\n\n## References\n\n1. [Unknown, Huntingtin structure and function (Cell 2020) (2020)](https://doi.org/10.1016/j.cell.2020.06.025)\n2. [Unknown, Huntington's disease pathogenesis (Nat Rev Neurosci 2021) (2021)](https://doi.org/10.1038/s41583-021-00478-0)",
  "entity_type": "protein"
}