Targeting aggregation in the development of therapeutics for the treatment of Huntington's disease and other polyglutamine repeat diseases
- PMID: 12667098
- DOI: 10.1517/14728222.7.2.201
Targeting aggregation in the development of therapeutics for the treatment of Huntington's disease and other polyglutamine repeat diseases
Abstract
Huntington's disease (HD) is one of a number of familial polyglutamine (polyQ) repeat diseases. These neurodegenerative disorders are caused by expression of otherwise unrelated proteins that contain an expansion of a polyQ tract, rendering them toxic to specific subsets of vulnerable neurons. These expanded repeats have an inherent propensity to aggregate; insoluble neuronal nuclear and cytoplasmic polyQ aggregates or inclusions are hallmarks of the disorders [1,2]. In HD, inclusions in diseased brains often precede onset of symptoms, and have been proposed to be involved in pathogenicity [3-5]. Various strategies to block the process of aggregation have been developed in an effort to create drugs that decrease neurotoxicity. A discussion of the effect of antibodies, caspase inhibitors, chemical inhibitors, heat-shock proteins, suppressor peptides and transglutaminase inhibitors upon aggregation and disease is presented.
Similar articles
-
Truncated N-terminal fragments of huntingtin with expanded glutamine repeats form nuclear and cytoplasmic aggregates in cell culture.Hum Mol Genet. 1998 May;7(5):783-90. doi: 10.1093/hmg/7.5.783. Hum Mol Genet. 1998. PMID: 9536081
-
Huntington's Disease.Cold Spring Harb Perspect Biol. 2011 Jun 1;3(6):a007476. doi: 10.1101/cshperspect.a007476. Cold Spring Harb Perspect Biol. 2011. PMID: 21441583 Free PMC article. Review.
-
Are neuronal intranuclear inclusions the common neuropathology of triplet-repeat disorders with polyglutamine-repeat expansions?Lancet. 1998 Jan 10;351(9096):131-3. doi: 10.1016/S0140-6736(97)08360-8. Lancet. 1998. PMID: 9439509
-
Amyloid formation by mutant huntingtin: threshold, progressivity and recruitment of normal polyglutamine proteins.Somat Cell Mol Genet. 1998 Jul;24(4):217-33. doi: 10.1023/b:scam.0000007124.19463.e5. Somat Cell Mol Genet. 1998. PMID: 10410676
-
Properties of polyglutamine expansion in vitro and in a cellular model for Huntington's disease.Philos Trans R Soc Lond B Biol Sci. 1999 Jun 29;354(1386):1013-9. doi: 10.1098/rstb.1999.0453. Philos Trans R Soc Lond B Biol Sci. 1999. PMID: 10434300 Free PMC article. Review.
Cited by
-
Xyloketal-derived small molecules show protective effect by decreasing mutant Huntingtin protein aggregates in Caenorhabditis elegans model of Huntington's disease.Drug Des Devel Ther. 2016 Apr 13;10:1443-51. doi: 10.2147/DDDT.S94666. eCollection 2016. Drug Des Devel Ther. 2016. PMID: 27110099 Free PMC article.
-
Wheel running from a juvenile age delays onset of specific motor deficits but does not alter protein aggregate density in a mouse model of Huntington's disease.BMC Neurosci. 2008 Apr 1;9:34. doi: 10.1186/1471-2202-9-34. BMC Neurosci. 2008. PMID: 18380890 Free PMC article.
-
Experimental models for identifying modifiers of polyglutamine-induced aggregation and neurodegeneration.Neurotherapeutics. 2013 Jul;10(3):400-15. doi: 10.1007/s13311-013-0195-4. Neurotherapeutics. 2013. PMID: 23700210 Free PMC article.
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Other Literature Sources
Medical