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When the mutant huntingtin was expressed in both astrocytes and neurons it worsened the phenotype relative to neuronal-only expression confirming the contribution of astroglia to HD (Jimenez-Sanchez et al. 2017). Mutant huntingtin also impacts the inflammatory response in the peripheral immune system which might explain the inflammation in HD (Jimenez-Sanchez et al. 2017).

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Evidence suggests that mutant huntingtin can interact with the outer mitochondrial membrane, resulting in mitochondrial calcium abnormalities as well as interfering with normal organellar axonal transport reducing the transportation of mitochondria to synapses and ATP production (Jimenez-Sanchez et al. 2017). Postmortem brains of HD patients show evidence of oxidative damage which can be a consequence of mitochondrial malfunction (Jimenez-Sanchez et al. 2017).

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Most cases of Huntington’s disease have alleles with 40-50 CAG repeats, and these patients exhibit symptoms like excessive uncontrolled muscle movement and gait disturbances, as well as neurological symptoms like depression, anxiety, and dementia (Finkbeiner 2011). There is a significant inverse relationship between the length of the repeating CAG segment and the age of onset of symptoms. The longer the segment, the earlier the onset. Patients with longer expansions (greater than 50 repeats) exhibit symptoms of bradykinesia, or slowness and hesitation of movements, and seizures. These cases are referred to as Juvenile Huntington’s Disorder (JHD) to recognize the difference in symptoms and the earlier onset (Finkbeiner 2011).

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Huntingtin is associated with synaptic vesicles in the presynaptic terminal (Jimenez-Sanchez et al. 2017). A recent study showed that huntingtin is required for the correct formation of cortical and striatal excitatory synapses (Jimenez-Sanchez et al. 2017).

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A well-known target of huntingtin-mediated transcriptional regulation is the gene encoding brain-derived neurotrophic factor (BDNF) (Jimenez-Sanchez et al. 2017). In the cytoplasm, huntingtin sequesters and inhibits the activity of REST/NRSF, a transcription factor that negatively regulates BDNF transcription (Jimenez-Sanchez et al. 2017).

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Huntingtin interacts with β-tubulin and binds to microtubules as well as interaction with dynein/dynactin complex (Jimenez-Sanchez et al. 2017). Huntingtin has also been shown to localize to spindle poles during mitosis, controlling spindle orientation (Jimenez-Sanchez et al. 2017).

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Recent studies have found that huntingtin plays a critical role in neurogenesis and is required for the maintenance of the lineage potential of primitive neuronal stem cells during neural induction (Jimenez-Sanchez et al. 2017). Furthermore, huntingtin has a crucial role in controlling homotypic interactions between neuroepithelial cells Jimenez-Sanchez et al. 2017).

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The mutant protein acts as a gain of function mutation because the altered huntingtin protein causes adverse effects.  Mutant huntingtin protein aggregates because the extended polyglutamine sequences form β-sheets, held together by hydrogen bonding, result in an insoluble amyloid structure. These aggregates accumulate, initially in the nucleus and later in the cytoplasm, and disrupt neurological function (Jimenez-Sanchez et al. 2017).

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Huntingtin has several key roles:

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Jimenez-Sanchez M, Licitra F, Underwood BR, Rubinsztein DC. Huntington's Disease: Mechanisms of Pathogenesis and Therapeutic Strategies. Cold Spring Harb Perspect Med. 2017 Jul 5;7(7):a024240. doi: 10.1101/cshperspect.a024240. PMID: 27940602; PMCID: PMC5495055.

Finkbeiner S. Huntington's Disease. Cold Spring Harb Perspect Biol. 2011 Jun 1;3(6):a007476. doi: 10.1101/cshperspect.a007476. PMID: 21441583; PMCID: PMC3098678.

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NH2 - Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln-
The resulting protein, huntingtin, has the polyglutamine sequence at the N-terminus (Jimenez-Sanchez et al. 2017).

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NH2 - Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln -

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5' - CAG CAG CAG CAG CAG CAG CAG CAG CAG CAG CAG CAG CAG CAG CAG CAG CAG CAG CAG CAG CAG CAG CAG CAG CAG CAG CAG CAG CAG CAG CAG CAG CAG CAG CAG CAG CAG CAG CAG CAG CAG CAG CAG CAG CAG CAG CAG CAG CAG CAG - 3'
50 CAG repeats. Mutated genes have an abnormally long sequence of CAG repeats

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5' - CAG CAG CAG CAG CAG CAG CAG CAG CAG CAG - 3'
10 CAG repeats. Wild type alleles can have up to 35 CAG repeats and maintain normal function of huntingtin.

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5' - CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG - 3'
Repeat expansion on the first exon of HTT

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5' - CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG - 3'
Small excerpt from the first exon of HTT

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Introduction:
Huntington's Disease (HD) is an autosomal dominant condition characterized by movement disorders and cognitive decline (Jimenez-Sanchez et al. 2017). HD is characterized by a general shrinkage of the brain and degeneration of the striatum (Jimenez-Sanchez et al. 2017). Huntington's Disease is due to mutations in the HTT gene encoding huntingtin, a ubiquitously expressed protein of 350 kDa which is found on chromosome 4 (Jimenez-Sanchez et al. 2017). The exact function of huntingtin is not fully known, but several of its roles have been described. It is necessary for embryonic development and neurogenesis, and it plays a role in transcriptional regulation. The prevalence of the mutation is four to ten cases per 100,000 of Western European origin (Jimenez-Sanchez et al. 2017).

Signs & Symptoms:
Symptoms include motor defects such as chorea and loss of coordination (Jimenez-Sanchez et al. 2017). Psychiatric symptoms, such as depression, psychosis, and obsessive-compulsive disorder, are also common in HD (Jimenez-Sanchez et al. 2017). Additional features are often present such as weight loss, skeletal-muscle wasting, and cardiac failure (Jimenez-Sanchez et al. 2017).