Therapeutic Approaches for Inhibition of Protein Aggregation in Huntington's Disease

Overview

Journal Exp Neurobiol

Specialty Neurology

Date 2014 Apr 17

PMID 24737938

Citations 16

Authors

Sangjune Kim

Kyong-Tai Kim

Affiliations

Soon will be listed here.

Abstract

Huntington's disease (HD) is a late-onset and progressive neurodegenerative disorder that is caused by aggregation of mutant huntingtin protein which contains expanded-polyglutamine. The molecular chaperones modulate the aggregation in early stage and known for the most potent protector of neurodegeneration in animal models of HD. Over the past decades, a number of studies have demonstrated molecular chaperones alleviate the pathogenic symptoms by polyQ-mediated toxicity. Moreover, chaperone-inducible drugs and anti-aggregation drugs have beneficial effects on symptoms of disease. Here, we focus on the function of molecular chaperone in animal models of HD, and review the recent therapeutic approaches to modulate expression and turn-over of molecular chaperone and to develop anti-aggregation drugs.

Citing Articles

Big versus small: The impact of aggregate size in disease.

Hnath B, Chen J, Reynolds J, Choi E, Wang J, Zhang D Protein Sci. 2023; 32(7):e4686.

PMID: 37243896 PMC: 10273386. DOI: 10.1002/pro.4686.

Carbon dots as a versatile tool to monitor insulin aggregation.

Zingale G, Distefano A, Pandino I, Tuccitto N, Oliveri V, Gaeta M Anal Bioanal Chem. 2023; 415(10):1829-1840.

PMID: 36808276 PMC: 10049934. DOI: 10.1007/s00216-023-04585-y.

Fragment-based virtual screening identifies a first-in-class preclinical drug candidate for Huntington's disease.

Galyan S, Ewald C, Jalencas X, Masrani S, Meral S, Mestres J Sci Rep. 2022; 12(1):19642.

PMID: 36385140 PMC: 9668931. DOI: 10.1038/s41598-022-21900-2.

Treatment with THI, an inhibitor of sphingosine-1-phosphate lyase, modulates glycosphingolipid metabolism and results therapeutically effective in experimental models of Huntington's disease.

Pepe G, Capocci L, Marracino F, Realini N, Lenzi P, Martinello K Mol Ther. 2022; 31(1):282-299.

PMID: 36116006 PMC: 9840122. DOI: 10.1016/j.ymthe.2022.09.004.

The Common Cellular Events in the Neurodegenerative Diseases and the Associated Role of Endoplasmic Reticulum Stress.

Kim S, Kim D, Jeong S, Lee J Int J Mol Sci. 2022; 23(11).

PMID: 35682574 PMC: 9180188. DOI: 10.3390/ijms23115894.

References

Bauer P, Nukina N . The pathogenic mechanisms of polyglutamine diseases and current therapeutic strategies. J Neurochem. 2009; 110(6):1737-65. DOI: 10.1111/j.1471-4159.2009.06302.x. View

Behrends C, Langer C, Boteva R, Bottcher U, Stemp M, Schaffar G . Chaperonin TRiC promotes the assembly of polyQ expansion proteins into nontoxic oligomers. Mol Cell. 2006; 23(6):887-97. DOI: 10.1016/j.molcel.2006.08.017. View

Tashiro E, Zako T, Muto H, Itoo Y, Sorgjerd K, Terada N . Prefoldin protects neuronal cells from polyglutamine toxicity by preventing aggregation formation. J Biol Chem. 2013; 288(27):19958-72. PMC: 3707696. DOI: 10.1074/jbc.M113.477984. View

Thakur A, Jayaraman M, Mishra R, Thakur M, Chellgren V, Byeon I . Polyglutamine disruption of the huntingtin exon 1 N terminus triggers a complex aggregation mechanism. Nat Struct Mol Biol. 2009; 16(4):380-9. PMC: 2706102. DOI: 10.1038/nsmb.1570. View

Dunah A, Jeong H, Griffin A, Kim Y, Standaert D, Hersch S . Sp1 and TAFII130 transcriptional activity disrupted in early Huntington's disease. Science. 2002; 296(5576):2238-43. DOI: 10.1126/science.1072613. View

Reiner A, Del Mar N, Deng Y, Meade C, Sun Z, Goldowitz D . R6/2 neurons with intranuclear inclusions survive for prolonged periods in the brains of chimeric mice. J Comp Neurol. 2007; 505(6):603-29. DOI: 10.1002/cne.21515. View

Bates E, Victor M, Jones A, Shi Y, Hart A . Differential contributions of Caenorhabditis elegans histone deacetylases to huntingtin polyglutamine toxicity. J Neurosci. 2006; 26(10):2830-8. PMC: 6675170. DOI: 10.1523/JNEUROSCI.3344-05.2006. View

Cattaneo E, Zuccato C, Tartari M . Normal huntingtin function: an alternative approach to Huntington's disease. Nat Rev Neurosci. 2005; 6(12):919-30. DOI: 10.1038/nrn1806. View

Hockly E, Richon V, Woodman B, Smith D, Zhou X, Rosa E . Suberoylanilide hydroxamic acid, a histone deacetylase inhibitor, ameliorates motor deficits in a mouse model of Huntington's disease. Proc Natl Acad Sci U S A. 2003; 100(4):2041-6. PMC: 149955. DOI: 10.1073/pnas.0437870100. View

10.

Caron N, Desmond C, Xia J, Truant R . Polyglutamine domain flexibility mediates the proximity between flanking sequences in huntingtin. Proc Natl Acad Sci U S A. 2013; 110(36):14610-5. PMC: 3767516. DOI: 10.1073/pnas.1301342110. View

11.

Jiang Y, Lv H, Liao M, Xu X, Huang S, Tan H . GRP78 counteracts cell death and protein aggregation caused by mutant huntingtin proteins. Neurosci Lett. 2012; 516(2):182-7. DOI: 10.1016/j.neulet.2012.03.074. View

12.

Chopra V, Fox J, Lieberman G, Dorsey K, Matson W, Waldmeier P . A small-molecule therapeutic lead for Huntington's disease: preclinical pharmacology and efficacy of C2-8 in the R6/2 transgenic mouse. Proc Natl Acad Sci U S A. 2007; 104(42):16685-9. PMC: 2034257. DOI: 10.1073/pnas.0707842104. View

13.

Muchowski P, Schaffar G, Sittler A, Wanker E, Hartl F . Hsp70 and hsp40 chaperones can inhibit self-assembly of polyglutamine proteins into amyloid-like fibrils. Proc Natl Acad Sci U S A. 2000; 97(14):7841-6. PMC: 16632. DOI: 10.1073/pnas.140202897. View

14.

van Roon-Mom W, Reid S, Jones A, MacDonald M, Faull R, Snell R . Insoluble TATA-binding protein accumulation in Huntington's disease cortex. Brain Res Mol Brain Res. 2003; 109(1-2):1-10. DOI: 10.1016/s0169-328x(02)00450-3. View

15.

Vashishtha M, Ng C, Yildirim F, Gipson T, Kratter I, Bodai L . Targeting H3K4 trimethylation in Huntington disease. Proc Natl Acad Sci U S A. 2013; 110(32):E3027-36. PMC: 3740882. DOI: 10.1073/pnas.1311323110. View

16.

Kim Y, Yi Y, Sapp E, Wang Y, Cuiffo B, Kegel K . Caspase 3-cleaved N-terminal fragments of wild-type and mutant huntingtin are present in normal and Huntington's disease brains, associate with membranes, and undergo calpain-dependent proteolysis. Proc Natl Acad Sci U S A. 2001; 98(22):12784-9. PMC: 60131. DOI: 10.1073/pnas.221451398. View

17.

Nasir J, Floresco S, OKusky J, Diewert V, Richman J, Zeisler J . Targeted disruption of the Huntington's disease gene results in embryonic lethality and behavioral and morphological changes in heterozygotes. Cell. 1995; 81(5):811-23. DOI: 10.1016/0092-8674(95)90542-1. View

18.

Perrin V, Regulier E, Abbas-Terki T, Hassig R, Brouillet E, Aebischer P . Neuroprotection by Hsp104 and Hsp27 in lentiviral-based rat models of Huntington's disease. Mol Ther. 2007; 15(5):903-11. DOI: 10.1038/mt.sj.6300141. View

19.

Fujimoto M, Takaki E, Hayashi T, Kitaura Y, Tanaka Y, Inouye S . Active HSF1 significantly suppresses polyglutamine aggregate formation in cellular and mouse models. J Biol Chem. 2005; 280(41):34908-16. DOI: 10.1074/jbc.M506288200. View

20.

Reed N, Cai D, Blasius T, Jih G, Meyhofer E, Gaertig J . Microtubule acetylation promotes kinesin-1 binding and transport. Curr Biol. 2006; 16(21):2166-72. DOI: 10.1016/j.cub.2006.09.014. View