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htt

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Official Full Name
huntingtin
Synonyms
HTT; huntingtin; HD protein homolog; Huntington disease gene homolog; huntington disease protein homolog; Hd; Hdh; IT15; AI256365; C430023I11Rik; ZHD; etID309952.1; SLC6A4

Recent Research Progress

HTT, huntingtin gene, which encodes the HTT protein and has a slightly higher expression levels in brain tissues (particularly in striatal neurons). Researchers have identified alternative splice variants, some of which produce pathogenic, truncated HTT fragments. The first HTT exon is suitable for the easily scalable CAG stretch coding of polyglutamine fragments. In the case of genetic instability, the number of CAG repeats increases, and once larger than ~35-37 repeats, it will be converted into a polyQ-amplified mutant protein responsible for HD episodes. Although HTT is conserved throughout evolution, the polyQ tail in exon 1 is not. This suggests that due to recent evolutionary achievements, HTT may play a role in the fine regulation of wild-type HTT function.

A recent research highlighted the age of onset, the clinical features of HD in exercise and cognitive impairment, the decline in viability, weight loss, the risk of death and neurodegeneration are related to their association with the length of CAG repeats of the HTT gene. Mutant HTT (mHTT) has a CAG repeat extension that encodes an unusually long polyglutamine (polyQ) repeat at the N-terminus of HTT. Neuronal pathology in HD is primarily due to the toxicity of mHTT and its protein hydrolysates, which form nuclear and cytoplasmic aggregates that disrupt nuclear gene transcription, RNA splicing and transport, and cell membrane dynamics. The neuropathological roles of mHTT have generally been considered to be cell-autonomous. Recent reports have, however, indicated that mHTT could be secreted by neurons, or transmitted from one neuronal cell to another through different unconventional modes of secretion, as well as through tunneled nanotubes (TNTs). These modes of propagation allow for intercellular communication of mHTT and its aggregates, thereby rationally promoting neuropathology between neurons within the proximal neuron population and within the neural circuits.

In normal human brain, HTT expression occurs in brain regions that are affected by cellular loss and neurodegeneration. However, HTT is also expressed throughout the brain at levels substantially above normalized gene expression levels of all human genes. In HD, behavioral dysfunctions and neurodegeneration occur in specific brain regions, the selectivity of HTT-mediated dysfunctions will involve the translation of mHTT protein and its unique cellular properties compared to normal HTT. Quantitative HTT gene expression patterns analyzed in normal adult human brain regions demonstrated its distribution is in areas known to undergo neurodegeneration in HD, as well as in other brain regions. Accordingly, investigation of the relationships between clinical HD profiles and the molecular mechanisms of mutant HTT will be important for understanding how mutant CAG expansions leads to devastating disabilities in HD patients.

Interestingly, Trajkovic K, et al. appointed out the lysosomal mechanism of mHTT secretion and offered a potential strategy for pharmacological modulation of neurosecretion. As the schematic diagram shown, secretion of one neuron (I) could occur via exosomes when luminal vesicles from the multivesicular body (MVB) fuse with the plasma membrane. These exosomes could be endocytosed by another neuron (II). Secretion could also occur via a lysosome-based mechanism, with the release of non-vesicular mHTT. Interneuronal transfer of mHTT, particularly between neurons (I and III) connected within a neural circuit, could occur via vesicles generated at the synaptic terminals. Intercellular transfer of mHTT aggregates could also be performed by tunneling nanotubes (TNTs). Moreover, mHTT secretion can be reduced significantly by phosphatidylinositol 3-kinase and neutral sphingomyelinase inhibitors. Noteworthily, understanding and manipulating the secretion of mHTT is important because of its potentially harmful propagation in the brain.

HTT Figure 1. Schematic diagram illustrating the various modes of mHTT (Tang B L. 2014).

References:

  1. Podvin S, et al. Multiple clinical features of Huntington’s disease correlate with mutant HTT gene CAG repeat lengths and neurodegeneration. Journal of Neurology, 2018:1-14.
  2. Stuitje G, et al. Age of onset in Huntington's disease is influenced by CAG repeat variations in other polyglutamine disease-associated genes. Brain, 2017, 140(7):e42.
  3. Trajkovic K, et al. Mutant huntingtin is secreted via a late endosomal/lysosomal unconventional secretory pathway. Journal of Neuroscience, 2017, 37(37):9000-9012.
  4. Tang B L. Unconventional Secretion and Intercellular Transfer of Mutant Huntingtin. Cells, 2018, 7(6):59.