Non-Cell Autonomous and Epigenetic Mechanisms of Huntington's Disease

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2021 Nov 27

PMID 34830381

Citations 5

Authors

Chaebin Kim

Ali Yousefian-Jazi

Seung-Hye Choi

Inyoung Chang

Junghee Lee

Hoon Ryu

Affiliations

Soon will be listed here.

Abstract

Huntington's disease (HD) is a rare neurodegenerative disorder caused by an expansion of CAG trinucleotide repeat located in the exon 1 of gene in human chromosome 4. The HTT protein is ubiquitously expressed in the brain. Specifically, mutant HTT (mHTT) protein-mediated toxicity leads to a dramatic degeneration of the striatum among many regions of the brain. HD symptoms exhibit a major involuntary movement followed by cognitive and psychiatric dysfunctions. In this review, we address the conventional role of wild type HTT (wtHTT) and how mHTT protein disrupts the function of medium spiny neurons (MSNs). We also discuss how mHTT modulates epigenetic modifications and transcriptional pathways in MSNs. In addition, we define how non-cell autonomous pathways lead to damage and death of MSNs under HD pathological conditions. Lastly, we overview therapeutic approaches for HD. Together, understanding of precise neuropathological mechanisms of HD may improve therapeutic approaches to treat the onset and progression of HD.

Citing Articles

Epigenetic Modifiers: Exploring the Roles of Histone Methyltransferases and Demethylases in Cancer and Neurodegeneration.

Reed L, Abraham J, Patel S, Dhar S Biology (Basel). 2025; 13(12.

PMID: 39765675 PMC: 11673268. DOI: 10.3390/biology13121008.

Coping with mortality salience: the role of connection thinking and afterlife beliefs in Chinese context.

Wang K, Sun Z, Hou Y, Yuan M Front Psychol. 2023; 14:1190906.

PMID: 38078250 PMC: 10704099. DOI: 10.3389/fpsyg.2023.1190906.

The Physio-Pathological Role of Group I Metabotropic Glutamate Receptors Expressed by Microglia in Health and Disease with a Focus on Amyotrophic Lateral Sclerosis.

Balbi M, Bonanno G, Bonifacino T, Milanese M Int J Mol Sci. 2023; 24(6).

PMID: 36982315 PMC: 10048889. DOI: 10.3390/ijms24065240.

Molecular Research on Huntington's Disease.

Valor L Int J Mol Sci. 2023; 24(5).

PMID: 36901739 PMC: 10002123. DOI: 10.3390/ijms24054310.

Therapeutic Strategies in Huntington's Disease: From Genetic Defect to Gene Therapy.

Jurcau A, Jurcau M Biomedicines. 2022; 10(8).

PMID: 36009443 PMC: 9405755. DOI: 10.3390/biomedicines10081895.

References

Damiano M, Galvan L, Deglon N, Brouillet E . Mitochondria in Huntington's disease. Biochim Biophys Acta. 2009; 1802(1):52-61. DOI: 10.1016/j.bbadis.2009.07.012. View

Bunner K, Rebec G . Corticostriatal Dysfunction in Huntington's Disease: The Basics. Front Hum Neurosci. 2016; 10:317. PMC: 4924423. DOI: 10.3389/fnhum.2016.00317. View

Franklin G, Camargo C, Meira A, Lima N, Teive H . The Role of the Cerebellum in Huntington's Disease: a Systematic Review. Cerebellum. 2020; 20(2):254-265. DOI: 10.1007/s12311-020-01198-4. View

Morfini G, Pigino G, Brady S . Polyglutamine expansion diseases: failing to deliver. Trends Mol Med. 2005; 11(2):64-70. DOI: 10.1016/j.molmed.2004.12.002. View

Jodeiri Farshbaf M, Ghaedi K . Huntington's Disease and Mitochondria. Neurotox Res. 2017; 32(3):518-529. DOI: 10.1007/s12640-017-9766-1. View

Garriga-Canut M, Agustin-Pavon C, Herrmann F, Sanchez A, Dierssen M, Fillat C . Synthetic zinc finger repressors reduce mutant huntingtin expression in the brain of R6/2 mice. Proc Natl Acad Sci U S A. 2012; 109(45):E3136-45. PMC: 3494930. DOI: 10.1073/pnas.1206506109. View

Cheng J, Liu H, Lin W, Tsai F . Identification of contributing genes of Huntington's disease by machine learning. BMC Med Genomics. 2020; 13(1):176. PMC: 7684976. DOI: 10.1186/s12920-020-00822-w. View

Lopes C, Tang Y, Anjo S, Manadas B, Onofre I, Almeida L . Mitochondrial and Redox Modifications in Huntington Disease Induced Pluripotent Stem Cells Rescued by CRISPR/Cas9 CAGs Targeting. Front Cell Dev Biol. 2020; 8:576592. PMC: 7536317. DOI: 10.3389/fcell.2020.576592. View

Pandey M, Rajamma U . Huntington's disease: the coming of age. J Genet. 2018; 97(3):649-664. View

10.

Faideau M, Kim J, Cormier K, Gilmore R, Welch M, Auregan G . In vivo expression of polyglutamine-expanded huntingtin by mouse striatal astrocytes impairs glutamate transport: a correlation with Huntington's disease subjects. Hum Mol Genet. 2010; 19(15):3053-67. PMC: 2901144. DOI: 10.1093/hmg/ddq212. View

11.

Arzberger T, Krampfl K, Leimgruber S, Weindl A . Changes of NMDA receptor subunit (NR1, NR2B) and glutamate transporter (GLT1) mRNA expression in Huntington's disease--an in situ hybridization study. J Neuropathol Exp Neurol. 1997; 56(4):440-54. DOI: 10.1097/00005072-199704000-00013. View

12.

Song W, Chen J, Petrilli A, Liot G, Klinglmayr E, Zhou Y . Mutant huntingtin binds the mitochondrial fission GTPase dynamin-related protein-1 and increases its enzymatic activity. Nat Med. 2011; 17(3):377-82. PMC: 3051025. DOI: 10.1038/nm.2313. View

13.

Tabrizi S, Flower M, Ross C, Wild E . Huntington disease: new insights into molecular pathogenesis and therapeutic opportunities. Nat Rev Neurol. 2020; 16(10):529-546. DOI: 10.1038/s41582-020-0389-4. View

14.

Yu D, Pendergraff H, Liu J, Kordasiewicz H, Cleveland D, Swayze E . Single-stranded RNAs use RNAi to potently and allele-selectively inhibit mutant huntingtin expression. Cell. 2012; 150(5):895-908. PMC: 3444165. DOI: 10.1016/j.cell.2012.08.002. View

15.

Sharma M, Rajendrarao S, Shahani N, Ramirez-Jarquin U, Subramaniam S . Cyclic GMP-AMP synthase promotes the inflammatory and autophagy responses in Huntington disease. Proc Natl Acad Sci U S A. 2020; 117(27):15989-15999. PMC: 7354937. DOI: 10.1073/pnas.2002144117. View

16.

Wang J, Chen Q, Wang X, Wang Q, Wang Y, Cheng H . Dysregulation of mitochondrial calcium signaling and superoxide flashes cause mitochondrial genomic DNA damage in Huntington disease. J Biol Chem. 2012; 288(5):3070-84. PMC: 3561531. DOI: 10.1074/jbc.M112.407726. View

17.

De Pietri Tonelli D, Pulvers J, Haffner C, Murchison E, Hannon G, Huttner W . miRNAs are essential for survival and differentiation of newborn neurons but not for expansion of neural progenitors during early neurogenesis in the mouse embryonic neocortex. Development. 2008; 135(23):3911-21. PMC: 2798592. DOI: 10.1242/dev.025080. View

18.

Qin Z, Wang Y, Sapp E, Cuiffo B, Wanker E, Hayden M . Huntingtin bodies sequester vesicle-associated proteins by a polyproline-dependent interaction. J Neurosci. 2004; 24(1):269-81. PMC: 6729557. DOI: 10.1523/JNEUROSCI.1409-03.2004. View

19.

Moller T . Neuroinflammation in Huntington's disease. J Neural Transm (Vienna). 2010; 117(8):1001-8. DOI: 10.1007/s00702-010-0430-7. View

20.

Jeon G, Kim K, Hwang Y, Jung M, An S, Ouchi M . Deregulation of BRCA1 leads to impaired spatiotemporal dynamics of γ-H2AX and DNA damage responses in Huntington's disease. Mol Neurobiol. 2012; 45(3):550-63. PMC: 4642996. DOI: 10.1007/s12035-012-8274-9. View