Polyglutamine-mediated Dysfunction and Apoptotic Death of a Caenorhabditis Elegans Sensory Neuron

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 1999 Jan 6

PMID 9874792

Citations 121

Authors

P W Faber

J R Alter

M E Macdonald

A C Hart

Affiliations

Soon will be listed here.

Abstract

The effect of expressing human huntingtin fragments containing polyglutamine (polyQ) tracts of varying lengths was assessed in Caenorhabditis elegans ASH sensory neurons in young and old animals. Expression of a huntingtin fragment containing a polyQ tract of 150 residues (Htn-Q150) led to progressive ASH neurodegeneration but did not cause cell death. Progressive cell death and enhanced neurodegeneration were observed in ASH neurons that coexpressed Htn-Q150 and a subthreshold dose of a toxic OSM-10::green fluorescent protein (OSM-10::GFP) fusion protein. Htn-Q150 huntingtin protein fragments formed protein aggregates in ASH neurons, and the number of ASH neurons containing aggregates increased as animals aged. ASH neuronal cell death required ced-3 caspase function, indicating that the observed cell death is apoptotic. Of interest, ced-3 played a critical role in Htn-Q150-mediated neurodegeneration but not in OSM10::GFP-mediated ASH neurodegeneration. ced-3 function was important but not essential for the formation of protein aggregates. Finally, behavioral assays indicated that ASH neurons, coexpressing Htn-Q150 and OSM10::GFP, were functionally impaired at 3 days before the detection of neurodegeneration, cell death, and protein aggregates.

Citing Articles

Downregulation of Pten Improves Huntington's Disease Phenotype by Reducing Htt Aggregates and Cell Death.

Nisha , Thapliyal D, Gohil B, Modak A, Singh N, Mukherjee C Mol Neurobiol. 2025; .

PMID: 40042729 DOI: 10.1007/s12035-025-04816-6.

Lipid Oxidation at the Crossroads: Oxidative Stress and Neurodegeneration Explored in .

Tortajada-Perez J, Carranza A, Trujillo-Del Rio C, Collado-Perez M, Millan J, Garcia-Garcia G Antioxidants (Basel). 2025; 14(1).

PMID: 39857412 PMC: 11762898. DOI: 10.3390/antiox14010078.

Quinic acid protects against the development of Huntington's disease in Caenorhabditis elegans model.

El Din R, Thabit S BMC Complement Med Ther. 2024; 24(1):377.

PMID: 39468600 PMC: 11514749. DOI: 10.1186/s12906-024-04670-4.

Olfactory dysfunction as an early pathogenic indicator in models of Alzheimer's and polyglutamine diseases.

Xue W, Lei Z, Liu B, Guo H, Yan W, Jin Y Front Aging Neurosci. 2024; 16:1462238.

PMID: 39411283 PMC: 11473296. DOI: 10.3389/fnagi.2024.1462238.

Towards Understanding Neurodegenerative Diseases: Insights from .

Wu Y, Chen Y, Yu X, Zhang M, Li Z Int J Mol Sci. 2024; 25(1).

PMID: 38203614 PMC: 10778690. DOI: 10.3390/ijms25010443.

References

Hart A, Sims S, Kaplan J . Synaptic code for sensory modalities revealed by C. elegans GLR-1 glutamate receptor. Nature. 1995; 378(6552):82-5. DOI: 10.1038/378082a0. View

Trottier Y, Lutz Y, Stevanin G, Imbert G, Devys D, Cancel G . Polyglutamine expansion as a pathological epitope in Huntington's disease and four dominant cerebellar ataxias. Nature. 1995; 378(6555):403-6. DOI: 10.1038/378403a0. View

Persichetti F, Ambrose C, Ge P, McNeil S, Srinidhi J, Anderson M . Normal and expanded Huntington's disease gene alleles produce distinguishable proteins due to translation across the CAG repeat. Mol Med. 1995; 1(4):374-83. PMC: 2230005. View

Mello C, Fire A . DNA transformation. Methods Cell Biol. 1995; 48:451-82. View

Gusella J, Macdonald M . Huntington's disease: CAG genetics expands neurobiology. Curr Opin Neurobiol. 1995; 5(5):656-62. DOI: 10.1016/0959-4388(95)80072-7. View

Ikeda H, Yamaguchi M, Sugai S, Aze Y, Narumiya S, Kakizuka A . Expanded polyglutamine in the Machado-Joseph disease protein induces cell death in vitro and in vivo. Nat Genet. 1996; 13(2):196-202. DOI: 10.1038/ng0696-196. View

Pulst S, Nechiporuk A, Nechiporuk T, Gispert S, Chen X, Lopes-Cendes I . Moderate expansion of a normally biallelic trinucleotide repeat in spinocerebellar ataxia type 2. Nat Genet. 1996; 14(3):269-76. DOI: 10.1038/ng1196-269. View

Sanpei K, Takano H, Igarashi S, Sato T, Oyake M, Sasaki H . Identification of the spinocerebellar ataxia type 2 gene using a direct identification of repeat expansion and cloning technique, DIRECT. Nat Genet. 1996; 14(3):277-84. DOI: 10.1038/ng1196-277. View

Imbert G, Saudou F, Yvert G, Devys D, Trottier Y, Garnier J . Cloning of the gene for spinocerebellar ataxia 2 reveals a locus with high sensitivity to expanded CAG/glutamine repeats. Nat Genet. 1996; 14(3):285-91. DOI: 10.1038/ng1196-285. View

10.

Hedgecock E, Culotti J, Thomson J, Perkins L . Axonal guidance mutants of Caenorhabditis elegans identified by filling sensory neurons with fluorescein dyes. Dev Biol. 1985; 111(1):158-70. DOI: 10.1016/0012-1606(85)90443-9. View

11.

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

12.

Perkins L, Hedgecock E, Thomson J, Culotti J . Mutant sensory cilia in the nematode Caenorhabditis elegans. Dev Biol. 1986; 117(2):456-87. DOI: 10.1016/0012-1606(86)90314-3. View

13.

Martin J, Gusella J . Huntington's disease. Pathogenesis and management. N Engl J Med. 1986; 315(20):1267-76. DOI: 10.1056/NEJM198611133152006. View

14.

Fire A, HARRISON S, Dixon D . A modular set of lacZ fusion vectors for studying gene expression in Caenorhabditis elegans. Gene. 1990; 93(2):189-98. DOI: 10.1016/0378-1119(90)90224-f. View

15.

La Spada A, Wilson E, Lubahn D, Harding A, Fischbeck K . Androgen receptor gene mutations in X-linked spinal and bulbar muscular atrophy. Nature. 1991; 352(6330):77-9. DOI: 10.1038/352077a0. View

16.

Han M, Sternberg P . Analysis of dominant-negative mutations of the Caenorhabditis elegans let-60 ras gene. Genes Dev. 1991; 5(12A):2188-98. DOI: 10.1101/gad.5.12a.2188. View

17.

Bargmann C, Thomas J, Horvitz H . Chemosensory cell function in the behavior and development of Caenorhabditis elegans. Cold Spring Harb Symp Quant Biol. 1990; 55:529-38. DOI: 10.1101/sqb.1990.055.01.051. View

18.

. 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

19.

Kaplan J, Horvitz H . A dual mechanosensory and chemosensory neuron in Caenorhabditis elegans. Proc Natl Acad Sci U S A. 1993; 90(6):2227-31. PMC: 46059. DOI: 10.1073/pnas.90.6.2227. View

20.

Orr H, Chung M, Banfi S, Kwiatkowski Jr T, Servadio A, Beaudet A . Expansion of an unstable trinucleotide CAG repeat in spinocerebellar ataxia type 1. Nat Genet. 1993; 4(3):221-6. DOI: 10.1038/ng0793-221. View