Huntington disease: new insights into molecular pathogenesis and therapeutic opportunities - PubMed (original) (raw)

Review

. 2020 Oct;16(10):529-546.

doi: 10.1038/s41582-020-0389-4. Epub 2020 Aug 14.

Affiliations

• PMID: 32796930
• DOI: 10.1038/s41582-020-0389-4

Review

Huntington disease: new insights into molecular pathogenesis and therapeutic opportunities

Sarah J Tabrizi et al. Nat Rev Neurol. 2020 Oct.

Abstract

Huntington disease (HD) is a neurodegenerative disease caused by CAG repeat expansion in the huntingtin gene (HTT) and involves a complex web of pathogenic mechanisms. Mutant HTT (mHTT) disrupts transcription, interferes with immune and mitochondrial function, and is aberrantly modified post-translationally. Evidence suggests that the mHTT RNA is toxic, and at the DNA level, somatic CAG repeat expansion in vulnerable cells influences the disease course. Genome-wide association studies have identified DNA repair pathways as modifiers of somatic instability and disease course in HD and other repeat expansion diseases. In animal models of HD, nucleocytoplasmic transport is disrupted and its restoration is neuroprotective. Novel cerebrospinal fluid (CSF) and plasma biomarkers are among the earliest detectable changes in individuals with premanifest HD and have the sensitivity to detect therapeutic benefit. Therapeutically, the first human trial of an HTT-lowering antisense oligonucleotide successfully, and safely, reduced the CSF concentration of mHTT in individuals with HD. A larger trial, powered to detect clinical efficacy, is underway, along with trials of other HTT-lowering approaches. In this Review, we discuss new insights into the molecular pathogenesis of HD and future therapeutic strategies, including the modulation of DNA repair and targeting the DNA mutation itself.

PubMed Disclaimer

Similar articles

• Mutant Huntingtin Is Cleared from the Brain via Active Mechanisms in Huntington Disease.
  Caron NS, Banos R, Yanick C, Aly AE, Byrne LM, Smith ED, Xie Y, Smith SEP, Potluri N, Findlay Black H, Casal L, Ko S, Cheung D, Kim H, Seong IS, Wild EJ, Song JJ, Hayden MR, Southwell AL. Caron NS, et al. J Neurosci. 2021 Jan 27;41(4):780-796. doi: 10.1523/JNEUROSCI.1865-20.2020. Epub 2020 Dec 11. J Neurosci. 2021. PMID: 33310753 Free PMC article.
• Cerebrospinal fluid mutant huntingtin is a biomarker for huntingtin lowering in the striatum of Huntington disease mice.
  Caron NS, Banos R, Aly AE, Xie Y, Ko S, Potluri N, Anderson C, Black HF, Anderson LM, Gordon B, Southwell AL, Hayden MR. Caron NS, et al. Neurobiol Dis. 2022 May;166:105652. doi: 10.1016/j.nbd.2022.105652. Epub 2022 Feb 7. Neurobiol Dis. 2022. PMID: 35143966 Free PMC article.
• Potent and sustained huntingtin lowering via AAV5 encoding miRNA preserves striatal volume and cognitive function in a humanized mouse model of Huntington disease.
  Caron NS, Southwell AL, Brouwers CC, Cengio LD, Xie Y, Black HF, Anderson LM, Ko S, Zhu X, van Deventer SJ, Evers MM, Konstantinova P, Hayden MR. Caron NS, et al. Nucleic Acids Res. 2020 Jan 10;48(1):36-54. doi: 10.1093/nar/gkz976. Nucleic Acids Res. 2020. PMID: 31745548 Free PMC article.
• Huntingtin Lowering Strategies for Disease Modification in Huntington's Disease.
  Tabrizi SJ, Ghosh R, Leavitt BR. Tabrizi SJ, et al. Neuron. 2019 Mar 6;101(5):801-819. doi: 10.1016/j.neuron.2019.01.039. Neuron. 2019. PMID: 30844400 Review.
• An insight into allele-selective approaches to lowering mutant huntingtin protein for Huntington's disease treatment.
  Yao JY, Liu T, Hu XR, Sheng H, Chen ZH, Zhao HY, Li XJ, Wang Y, Hao L. Yao JY, et al. Biomed Pharmacother. 2024 Nov;180:117557. doi: 10.1016/j.biopha.2024.117557. Epub 2024 Oct 13. Biomed Pharmacother. 2024. PMID: 39405896 Review.

Cited by

• Role of Thrombosis in Neurodegenerative Diseases: An Intricate Mechanism of Neurovascular Complications.
  Beura SK, Panigrahi AR, Yadav P, Kulkarni PP, Lakhanpal V, Singh B, Singh SK. Beura SK, et al. Mol Neurobiol. 2024 Nov 1. doi: 10.1007/s12035-024-04589-4. Online ahead of print. Mol Neurobiol. 2024. PMID: 39482419 Review.
• Dose-dependent reduction of somatic expansions but not Htt aggregates by di-valent siRNA-mediated silencing of MSH3 in HdhQ111 mice.
  Driscoll R, Hampton L, Abraham NA, Larigan JD, Joseph NF, Hernandez-Vega JC, Geisler S, Yang FC, Deninger M, Tran DT, Khatri N, Godinho BMDC, Kinberger GA, Montagna DR, Hirst WD, Guardado CL, Glajch KE, Arnold HM, Gallant-Behm CL, Weihofen A. Driscoll R, et al. Sci Rep. 2024 Jan 24;14(1):2061. doi: 10.1038/s41598-024-52667-3. Sci Rep. 2024. PMID: 38267530 Free PMC article.
• Current Diagnostic Methods and Non-Coding RNAs as Possible Biomarkers in Huntington's Disease.
  Pellegrini M, Bergonzoni G, Perrone F, Squitieri F, Biagioli M. Pellegrini M, et al. Genes (Basel). 2022 Nov 3;13(11):2017. doi: 10.3390/genes13112017. Genes (Basel). 2022. PMID: 36360254 Free PMC article. Review.
• Huntington's Disease Gene Hunters: An Expanding Tale.
  Rosser AE, Jones L. Rosser AE, et al. Mov Disord Clin Pract. 2021 Dec 16;9(3):330-333. doi: 10.1002/mdc3.13375. eCollection 2022 Apr. Mov Disord Clin Pract. 2021. PMID: 35392298 Free PMC article. No abstract available.
• Normal range CAG repeat size variations in the HTT gene are associated with an adverse lipoprotein profile partially mediated by body mass index.
  Faquih TO, Aziz NA, Gardiner SL, Li-Gao R, de Mutsert R, Milaneschi Y, Trompet S, Jukema JW, Rosendaal FR, van Hylckama Vlieg A, van Dijk KW, Mook-Kanamori DO. Faquih TO, et al. Hum Mol Genet. 2023 May 5;32(10):1741-1752. doi: 10.1093/hmg/ddad020. Hum Mol Genet. 2023. PMID: 36715614 Free PMC article.

References

1. 1. Bates, G. P. et al. Huntington disease. Nat. Rev. Dis. Primers 1, 1–21 (2015).
2. 1. Paulson, H. Repeat expansion diseases. Handb. Clin. Neurol. 147, 105–123 (2018). - PubMed - PMC
3. 1. Evans, S. J. et al. Prevalence of adult Huntington’s disease in the UK based on diagnoses recorded in general practice records. J. Neurol. Neurosurg. Psychiatry 84, 1156–1160 (2013). - PubMed - PMC
4. 1. Langbehn, D. R., Hayden, M. R. & Paulsen, J. S. CAG-repeat length and the age of onset in Huntington disease (HD): a review and validation study of statistical approaches. Am. J. Med. Genet. B Neuropsychiatr. Genet. 153b, 397–408 (2010). - PubMed - PMC
5. 1. Ross, C. A. et al. Huntington disease: natural history, biomarkers and prospects for therapeutics. Nat. Rev. Neurol. 10, 204–216 (2014). - PubMed

Publication types

MeSH terms

Substances

LinkOut - more resources

• Full Text Sources

  • Nature Publishing Group

• Other Literature Sources

  • The Lens - Patent Citations Database

• Medical

  • MedlinePlus Health Information