Death of Neuronal Clusters Contributes to Variance of Age at Onset in Huntington's Disease

Overview

Journal Neurogenetics

Specialty Neurology

Date 2006 Jan 18

PMID 16416264

Citations 4

Authors

Branka Cajavec

Hanspeter Herzel

Samuel Bernard

Affiliations

Soon will be listed here.

Abstract

Huntington's disease (HD) is a fatal neurodegenerative disease caused by an expanded polyglutamine (polyQ) repeat in the protein huntingtin. Due to selective neuronal loss in the cortex and striatum, HD patients develop various movement disturbances, psychological changes, and dementia. Symptoms usually appear in individuals between 30 and 50 years of age. The principal cause of variability of age at onset (AO) is the length of the polyQ repeat. Several additional genetic factors contributing to the variance have been identified. At least 35% of the variance, however, remains unexplained. Using a stochastic model, we show that the pattern of cell death of striatal neurons might contribute up to 20% of variance of AO.

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References

Andrews T, Weeks R, Turjanski N, Gunn R, Watkins L, Sahakian B . Huntington's disease progression. PET and clinical observations. Brain. 1999; 122 ( Pt 12):2353-63. DOI: 10.1093/brain/122.12.2353. View

Perutz M, Windle A . Cause of neural death in neurodegenerative diseases attributable to expansion of glutamine repeats. Nature. 2001; 412(6843):143-4. DOI: 10.1038/35084141. View

Augood S, Faull R, Emson P . Dopamine D1 and D2 receptor gene expression in the striatum in Huntington's disease. Ann Neurol. 1997; 42(2):215-21. DOI: 10.1002/ana.410420213. View

Rubinsztein D, Leggo J, Chiano M, Dodge A, Norbury G, Rosser E . Genotypes at the GluR6 kainate receptor locus are associated with variation in the age of onset of Huntington disease. Proc Natl Acad Sci U S A. 1997; 94(8):3872-6. PMC: 20534. DOI: 10.1073/pnas.94.8.3872. View

Kieburtz K, MacDonald M, Shih C, Feigin A, Steinberg K, Bordwell K . Trinucleotide repeat length and progression of illness in Huntington's disease. J Med Genet. 1994; 31(11):872-4. PMC: 1016662. DOI: 10.1136/jmg.31.11.872. View

Langbehn D, Brinkman R, Falush D, Paulsen J, Hayden M . A new model for prediction of the age of onset and penetrance for Huntington's disease based on CAG length. Clin Genet. 2004; 65(4):267-77. DOI: 10.1111/j.1399-0004.2004.00241.x. View

Rosas H, Goodman J, Chen Y, Jenkins B, Kennedy D, Makris N . Striatal volume loss in HD as measured by MRI and the influence of CAG repeat. Neurology. 2001; 57(6):1025-8. DOI: 10.1212/wnl.57.6.1025. View

Squitieri F, Sabbadini G, Mandich P, Gellera C, Di Maria E, Bellone E . Family and molecular data for a fine analysis of age at onset in Huntington disease. Am J Med Genet. 2001; 95(4):366-73. DOI: 10.1002/1096-8628(20001211)95:4<366::aid-ajmg13>3.0.co;2-2. View

Rosenblatt A, Brinkman R, Liang K, Almqvist E, Margolis R, Huang C . Familial influence on age of onset among siblings with Huntington disease. Am J Med Genet. 2001; 105(5):399-403. View

10.

Andrew S, Goldberg Y, Kremer B, Telenius H, Theilmann J, Adam S . The relationship between trinucleotide (CAG) repeat length and clinical features of Huntington's disease. Nat Genet. 1993; 4(4):398-403. DOI: 10.1038/ng0893-398. View

11.

Nahhas F, Garbern J, Krajewski K, Roa B, Feldman G . Juvenile onset Huntington disease resulting from a very large maternal expansion. Am J Med Genet A. 2005; 137A(3):328-31. DOI: 10.1002/ajmg.a.30891. View

12.

Thieben M, Duggins A, Good C, Gomes L, Mahant N, Richards F . The distribution of structural neuropathology in pre-clinical Huntington's disease. Brain. 2002; 125(Pt 8):1815-28. DOI: 10.1093/brain/awf179. View

13.

Margolis R, Ross C . Diagnosis of Huntington disease. Clin Chem. 2003; 49(10):1726-32. DOI: 10.1373/49.10.1726. View

14.

Snell R, MacMillan J, Cheadle J, Fenton I, Lazarou L, Davies P . Relationship between trinucleotide repeat expansion and phenotypic variation in Huntington's disease. Nat Genet. 1993; 4(4):393-7. DOI: 10.1038/ng0893-393. View

15.

Clarke G, Collins R, Leavitt B, ANDREWS D, Hayden M, Lumsden C . A one-hit model of cell death in inherited neuronal degenerations. Nature. 2000; 406(6792):195-9. DOI: 10.1038/35018098. View

16.

. 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. 1993; 72(6):971-83. DOI: 10.1016/0092-8674(93)90585-e. View

17.

Vonsattel J, Myers R, Stevens T, Ferrante R, BIRD E, Richardson Jr E . Neuropathological classification of Huntington's disease. J Neuropathol Exp Neurol. 1985; 44(6):559-77. DOI: 10.1097/00005072-198511000-00003. View

18.

Hedreen J, Folstein S . Early loss of neostriatal striosome neurons in Huntington's disease. J Neuropathol Exp Neurol. 1995; 54(1):105-20. DOI: 10.1097/00005072-199501000-00013. View

19.

Chattopadhyay B, Baksi K, Mukhopadhyay S, Bhattacharyya N . Modulation of age at onset of Huntington disease patients by variations in TP53 and human caspase activated DNase (hCAD) genes. Neurosci Lett. 2005; 374(2):81-6. DOI: 10.1016/j.neulet.2004.10.018. View

20.

Arning L, Kraus P, Valentin S, Saft C, Andrich J, Epplen J . NR2A and NR2B receptor gene variations modify age at onset in Huntington disease. Neurogenetics. 2005; 6(1):25-8. DOI: 10.1007/s10048-004-0198-8. View