Biology:Huntingtin

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Short description: Gene and protein involved in Huntington's disease


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

Huntingtin (Htt) is the protein coded for in humans by the HTT gene, also known as the IT15 ("interesting transcript 15") gene.[1] Mutated HTT is the cause of Huntington's disease (HD), and has been investigated for this role and also for its involvement in long-term memory storage.[2]

It is variable in its structure, as the many polymorphisms of the gene can lead to variable numbers of glutamine residues present in the protein. In its wild-type (normal) form, the polymorphic locus contains 6-35 glutamine residues. However, in individuals affected by Huntington's disease (an autosomal dominant genetic disorder), the polymorphic locus contains more than 36 glutamine residues (highest reported repeat length is about 250).[3] Its commonly used name is derived from this disease; previously, the IT15 label was commonly used.

The mass of huntingtin protein is dependent largely on the number of glutamine residues it has; the predicted mass is around 350 kDa. Normal huntingtin is generally accepted to be 3144 amino acids in size. The exact function of this protein is not known, but it plays an important role in nerve cells. Within cells, huntingtin may or may not be involved in signaling, transporting materials, binding proteins and other structures, and protecting against apoptosis, a form of programmed cell death. The huntingtin protein is required for normal development before birth.[4] It is expressed in many tissues in the body, with the highest levels of expression seen in the brain.

Gene

The 5'-end (five prime end) of the HTT gene has a sequence of three DNA bases, cytosine-adenine-guanine (CAG), coding for the amino acid glutamine, that is repeated multiple times. This region is called a trinucleotide repeat. The usual CAG repeat count is between seven and 35 repeats.

The HTT gene is located on the short arm (p) of chromosome 4 at position 16.3, from base pair 3,074,510 to base pair 3,243,960.[5]

Protein

Function

The function of huntingtin (Htt) is not well understood but it is involved in axonal transport.[6] Huntingtin is essential for development, and its absence is lethal in mice.[4] The protein has no sequence homology with other proteins and is highly expressed in neurons and testes in humans and rodents.[7] Huntingtin upregulates the expression of brain-derived neurotrophic factor (BDNF) at the transcription level, but the mechanism by which huntingtin regulates gene expression has not been determined.[8] From immunohistochemistry, electron microscopy, and subcellular fractionation studies of the molecule, it has been found that huntingtin is primarily associated with vesicles and microtubules.[9][10] These appear to indicate a functional role in cytoskeletal anchoring or transport of mitochondria. The Htt protein is involved in vesicle trafficking as it interacts with HIP1, a clathrin-binding protein, to mediate endocytosis, the trafficking of materials into a cell.[11][12] Huntingtin has also been shown to have a role in the establishment in epithelial polarity through its interaction with RAB11A.[13]

Interactions

Huntingtin has been found to interact directly with at least 19 other proteins, of which six are used for transcription, four for transport, three for cell signalling, and six others of unknown function (HIP5, HIP11, HIP13, HIP15, HIP16, and CGI-125).[14] Over 100 interacting proteins have been found, such as huntingtin-associated protein 1 (HAP1) and huntingtin interacting protein 1 (HIP1), these were typically found using two-hybrid screening and confirmed using immunoprecipitation.[15][16]

Interacting Protein PolyQ length dependence Function
α-adaptin C/HYPJ Yes Endocytosis
Akt/PKB No Kinase
CBP Yes Transcriptional co-activator with acetyltransferase activity
CA150 No Transcriptional activator
CIP4 Yes cdc42-dependent signal transduction
CtBP Yes Transcription factor
FIP2 Not known Cell morphogenesis
Grb2[17] Not known Growth factor receptor binding protein
HAP1 Yes Membrane trafficking
HAP40 (F8A1, F8A2, F8A3) Not known Unknown
HIP1 Yes Endocytosis, proapoptotic
HIP14/HYP-H Yes Trafficking, endocytosis
N-CoR Yes Nuclear receptor co-repressor
NF-κB Not known Transcription factor
p53[18] No Transcription factor
PACSIN1[19] Yes Endocytosis, actin cytoskeleton
DLG4 (PSD-95) Yes Postsynaptic Density 95
RASA1 (RasGAP)[17] Not known Ras GTPase activating protein
SH3GL3[20] Yes Endocytosis
SIN3A Yes Transcriptional repressor
Sp1[21] Yes Transcription factor

Huntingtin has also been shown to interact with:


Mitochondrial dysfunction

Huntingtin is a scaffolding protein in the ATM oxidative DNA damage response complex. Mutant huntingtin (mHtt) plays a key role in mitochondrial dysfunction involving the inhibition of mitochondrial electron transport, higher levels of reactive oxygen species and increased oxidative stress.[28][29] The promotion of oxidative damage to DNA may contribute to Huntington's disease pathology.[30]

Clinical significance

Main page: Medicine:Huntington's disease
Classification of the trinucleotide repeat, and resulting disease status, depends on the number of CAG repeats[31]
Repeat count Classification Disease status
<26 Normal Unaffected
27–35 Intermediate Unaffected
36–40 Reduced penetrance +/- Affected
>40 Full penetrance Affected

Huntington's disease (HD) is caused by a mutated form of the huntingtin gene, where excessive (more than 36) CAG repeats result in formation of an unstable protein.[31] These expanded repeats lead to production of a huntingtin protein that contains an abnormally long polyglutamine tract at the N-terminus. This makes it part of a class of neurodegenerative disorders known as trinucleotide repeat disorders or polyglutamine disorders. The key sequence which is found in Huntington's disease is a trinucleotide repeat expansion of glutamine residues beginning at the 18th amino acid. In unaffected individuals, this contains between 9 and 35 glutamine residues with no adverse effects.[1] However, 36 or more residues produce an erroneous mutant form of Htt, (mHtt). Reduced penetrance is found in counts 36–39.[32]

Enzymes in the cell often cut this elongated protein into fragments. The protein fragments form abnormal clumps, known as neuronal intranuclear inclusions (NIIs), inside nerve cells, and may attract other, normal proteins into the clumps. The characteristic presence of these clumps in patients was thought to contribute to the development of Huntington disease.[33] However, later research raised questions about the role of the inclusions (clumps) by showing the presence of visible NIIs extended the life of neurons and acted to reduce intracellular mutant huntingtin in neighboring neurons.[34] One confounding factor is that different types of aggregates are now recognised to be formed by the mutant protein, including protein deposits that are too small to be recognised as visible deposits in the above-mentioned studies.[35] The likelihood of neuronal death remains difficult to predict. Likely multiple factors are important, including: (1) the length of CAG repeats in the huntingtin gene and (2) the neuron's exposure to diffuse intracellular mutant huntingtin protein. NIIs (protein clumping) can be helpful as a coping mechanism—and not simply a pathogenic mechanism—to stem neuronal death by decreasing the amount of diffuse huntingtin.[36] This process is particularly likely to occur in the striatum (a part of the brain that coordinates movement) primarily, and the frontal cortex (a part of the brain that controls thinking and emotions).

People with 36 to 40 CAG repeats may or may not develop the signs and symptoms of Huntington disease, while people with more than 40 repeats will develop the disorder during a normal lifetime. When there are more than 60 CAG repeats, the person develops a severe form of HD known as juvenile HD. Therefore, the number of CAG (the sequence coding for the amino acid glutamine) repeats influences the age of onset of the disease. No case of HD has been diagnosed with a count less than 36.[32]

As the altered gene is passed from one generation to the next, the size of the CAG repeat expansion can change; it often increases in size, especially when it is inherited from the father. People with 28 to 35 CAG repeats have not been reported to develop the disorder, but their children are at risk of having the disease if the repeat expansion increases.

References

  1. ↑ 1.0 1.1 The Huntington's Disease Collaborative Research Group (Mar 1993). "A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. The Huntington's Disease Collaborative Research Group". Cell 72 (6): 971–83. doi:10.1016/0092-8674(93)90585-E. PMID 8458085. https://deepblue.lib.umich.edu/bitstream/2027.42/30901/3/0000570.pdf. Retrieved 2019-08-29. 
  2. ↑ "Huntingtin is critical both pre- and postsynaptically for long-term learning-related synaptic plasticity in Aplysia". PLOS ONE 9 (7): e103004. July 23, 2014. doi:10.1371/journal.pone.0103004. PMID 25054562. Bibcode: 2014PLoSO...9j3004C. 
  3. ↑ "Analysis of a very large trinucleotide repeat in a patient with juvenile Huntington's disease". Neurology 52 (2): 392–4. Jan 1999. doi:10.1212/wnl.52.2.392. PMID 9932964. http://www.neurology.org/cgi/content/abstract/52/2/392. Retrieved 2009-05-02. 
  4. ↑ 4.0 4.1 "Targeted disruption of the Huntington's disease gene results in embryonic lethality and behavioral and morphological changes in heterozygotes". Cell 81 (5): 811–23. Jun 1995. doi:10.1016/0092-8674(95)90542-1. PMID 7774020. 
  5. ↑ "HTT gene". http://ghr.nlm.nih.gov/gene/HTT. 
  6. ↑ "Traffic signaling: new functions of huntingtin and axonal transport in neurological disease". Current Opinion in Neurobiology 63: 122–130. August 2020. doi:10.1016/j.conb.2020.04.001. PMID 32408142. 
  7. ↑ "Normal huntingtin function: an alternative approach to Huntington's disease". Nature Reviews. Neuroscience 6 (12): 919–30. December 2005. doi:10.1038/nrn1806. PMID 16288298. 
  8. ↑ "Loss of huntingtin-mediated BDNF gene transcription in Huntington's disease". Science 293 (5529): 493–8. July 2001. doi:10.1126/science.1059581. PMID 11408619. 
  9. ↑ "Perinuclear localization of huntingtin as a consequence of its binding to microtubules through an interaction with beta-tubulin: relevance to Huntington's disease". Journal of Cell Science 115 (Pt 5): 941–8. March 2002. doi:10.1242/jcs.115.5.941. PMID 11870213. 
  10. ↑ "Huntingtin is a cytoplasmic protein associated with vesicles in human and rat brain neurons". Neuron 14 (5): 1075–81. May 1995. doi:10.1016/0896-6273(95)90346-1. PMID 7748555. 
  11. ↑ "Wild-type and mutant huntingtins function in vesicle trafficking in the secretory and endocytic pathways". Experimental Neurology 152 (1): 34–40. July 1998. doi:10.1006/exnr.1998.6832. PMID 9682010. 
  12. ↑ "The huntingtin interacting protein HIP1 is a clathrin and alpha-adaptin-binding protein involved in receptor-mediated endocytosis". Human Molecular Genetics 10 (17): 1807–17. August 2001. doi:10.1093/hmg/10.17.1807. PMID 11532990. 
  13. ↑ "Huntingtin Is Required for Epithelial Polarity through RAB11A-Mediated Apical Trafficking of PAR3-aPKC". PLOS Biology 13 (5): e1002142. May 2015. doi:10.1371/journal.pbio.1002142. PMID 25942483. 
  14. ↑ "The hunt for huntingtin function: interaction partners tell many different stories". Trends in Biochemical Sciences 28 (8): 425–33. Aug 2003. doi:10.1016/S0968-0004(03)00168-3. PMID 12932731. 
  15. ↑ "A protein interaction network links GIT1, an enhancer of huntingtin aggregation, to Huntington's disease". Molecular Cell 15 (6): 853–65. Sep 2004. doi:10.1016/j.molcel.2004.09.016. PMID 15383276. 
  16. ↑ "HIP-I: a huntingtin interacting protein isolated by the yeast two-hybrid system". Human Molecular Genetics 6 (3): 487–95. Mar 1997. doi:10.1093/hmg/6.3.487. PMID 9147654. 
  17. ↑ 17.0 17.1 "SH3 domain-dependent association of huntingtin with epidermal growth factor receptor signaling complexes". The Journal of Biological Chemistry 272 (13): 8121–4. Mar 1997. doi:10.1074/jbc.272.13.8121. PMID 9079622. 
  18. ↑ "The Huntington's disease protein interacts with p53 and CREB-binding protein and represses transcription". Proceedings of the National Academy of Sciences of the United States of America 97 (12): 6763–8. Jun 2000. doi:10.1073/pnas.100110097. PMID 10823891. Bibcode: 2000PNAS...97.6763S. 
  19. ↑ "PACSIN 1 interacts with huntingtin and is absent from synaptic varicosities in presymptomatic Huntington's disease brains". Human Molecular Genetics 11 (21): 2547–58. Oct 2002. doi:10.1093/hmg/11.21.2547. PMID 12354780. 
  20. ↑ "SH3GL3 associates with the Huntingtin exon 1 protein and promotes the formation of polygln-containing protein aggregates". Molecular Cell 2 (4): 427–36. Oct 1998. doi:10.1016/S1097-2765(00)80142-2. PMID 9809064. 
  21. ↑ "Interaction of Huntington disease protein with transcriptional activator Sp1". Molecular and Cellular Biology 22 (5): 1277–87. Mar 2002. doi:10.1128/MCB.22.5.1277-1287.2002. PMID 11839795. 
  22. ↑ "Huntingtin is ubiquitinated and interacts with a specific ubiquitin-conjugating enzyme". The Journal of Biological Chemistry 271 (32): 19385–94. Aug 1996. doi:10.1074/jbc.271.32.19385. PMID 8702625. 
  23. ↑ "Activation of MLK2-mediated signaling cascades by polyglutamine-expanded huntingtin". The Journal of Biological Chemistry 275 (25): 19035–40. Jun 2000. doi:10.1074/jbc.C000180200. PMID 10801775. 
  24. ↑ "FIP-2, a coiled-coil protein, links Huntingtin to Rab8 and modulates cellular morphogenesis". Current Biology 10 (24): 1603–6. 2000. doi:10.1016/S0960-9822(00)00864-2. PMID 11137014. 
  25. ↑ 25.0 25.1 25.2 "Huntingtin interacts with a family of WW domain proteins". Human Molecular Genetics 7 (9): 1463–74. Sep 1998. doi:10.1093/hmg/7.9.1463. PMID 9700202. 
  26. ↑ "Cdc42-interacting protein 4 binds to huntingtin: neuropathologic and biological evidence for a role in Huntington's disease". Proceedings of the National Academy of Sciences of the United States of America 100 (5): 2712–7. Mar 2003. doi:10.1073/pnas.0437967100. PMID 12604778. Bibcode: 2003PNAS..100.2712H. 
  27. ↑ "HIP14, a novel ankyrin domain-containing protein, links huntingtin to intracellular trafficking and endocytosis". Human Molecular Genetics 11 (23): 2815–28. Nov 2002. doi:10.1093/hmg/11.23.2815. PMID 12393793. 
  28. ↑ "Oxidative Stress in Neurodegenerative Diseases: From Molecular Mechanisms to Clinical Applications". Oxid Med Cell Longev 2017: 2525967. 2017. doi:10.1155/2017/2525967. PMID 28785371. 
  29. ↑ Maiuri, Tamara; Mocle, Andrew J.; Hung, Claudia L.; Xia, Jianrun; van Roon-Mom, Willeke M. C.; Truant, Ray (25 December 2016). "Huntingtin is a scaffolding protein in the ATM oxidative DNA damage response complex". Human Molecular Genetics 26 (2): 395–406. doi:10.1093/hmg/ddw395. PMID 28017939. 
  30. ↑ "Role of oxidative DNA damage in mitochondrial dysfunction and Huntington's disease pathogenesis". Free Radic. Biol. Med. 62: 102–10. September 2013. doi:10.1016/j.freeradbiomed.2013.04.017. PMID 23602907. 
  31. ↑ 31.0 31.1 "Huntington's disease". Lancet 369 (9557): 218–28. Jan 2007. doi:10.1016/S0140-6736(07)60111-1. PMID 17240289. 
  32. ↑ 32.0 32.1 "Contribution of DNA sequence and CAG size to mutation frequencies of intermediate alleles for Huntington disease: evidence from single sperm analyses". Human Molecular Genetics 6 (2): 301–9. Feb 1997. doi:10.1093/hmg/6.2.301. PMID 9063751. 
  33. ↑ "Formation of neuronal intranuclear inclusions underlies the neurological dysfunction in mice transgenic for the HD mutation". Cell 90 (3): 537–48. Aug 1997. doi:10.1016/S0092-8674(00)80513-9. PMID 9267033. 
  34. ↑ "Inclusion body formation reduces levels of mutant huntingtin and the risk of neuronal death". Nature 431 (7010): 805–10. Oct 2004. doi:10.1038/nature02998. PMID 15483602. Bibcode: 2004Natur.431..805A. 
  35. ↑ "Delayed Emergence of Subdiffraction-Sized Mutant Huntingtin Fibrils Following Inclusion Body Formation". Q Rev Biophys 49: e2. 2016. doi:10.1017/S0033583515000219. PMID 26350150. 
  36. ↑ "Neurodegenerative disease: neuron protection agency". Nature 431 (7010): 747–8. Oct 2004. doi:10.1038/431747a. PMID 15483586. Bibcode: 2004Natur.431..747O. 

Further reading

External links



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