Clinical Aspects of CAG Repeat Diseases

Nance, Martha

doi:10.1111/j.1750-3639.1997.tb00892.x

Cited by 78 publications

(35 citation statements)

References 161 publications

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“…The Q19-GFP construct was designed to be representative of wild-type protein, because normal individuals typically have fewer than 35 [CAG] repeat lengths in the various disease genes (for review, see Nance, 1997). Accordingly, Q19-GFP was never observed to aggregate in rat granule cells at the level of conventional fluorescence microscopy ( Figs.…”

Section: Characteristics Of Polyglutamine-gfp Fusion Protein Aggregatmentioning

confidence: 99%

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Generation of Neuronal Intranuclear Inclusions by Polyglutamine-GFP: Analysis of Inclusion Clearance and Toxicity as a Function of Polyglutamine Length

et al. 1999

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Recent evidence suggests that, in huntingtin and many other proteins, polyglutamine repeats are a toxic stimulus in neurodegenerative diseases. To investigate the mechanism by which these repeats may be toxic, we transfected primary rat cerebellar granule neurons with polyglutamine-green fluorescent protein (GFP) fusion constructs containing 19 (Q19-GFP), 35 (Q35-GFP), 56 (Q56-GFP), or 80 (Q80-GFP) glutamine residues. All constructs, except Q19-GFP, aggregated within the nuclei of transfected cells in a length-and time-dependent manner. Although Q35-GFP expression led to the development of several small aggregates per cell, these aggregates were cleared or degraded, and the cells remained viable. In contrast, Q80-GFP expression resulted in one or two large aggregates and induced cell death. Caspase activation was observed after Q80-GFP aggregation, but inhibition of caspases with Boc-aspartyl-(OMe)-fluoromethylketone (BAF) only served to delay, not prevent, toxicity. In addition, aggregation and toxicity were not affected by other modulators of neuronal cell death such as genetic deletion of the proapoptotic bcl-2 family member bax or addition of the protein synthesis inhibitor cycloheximide. Lastly, nuclear condensation did not occur as part of the toxicity. These data suggest that polyglutamine-GFP expression is toxic to primary neurons but that the death is distinct from classical apoptosis.

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Section: Characteristics Of Polyglutamine-gfp Fusion Protein Aggregatmentioning

confidence: 99%

“…Individuals with 31-39 [CAG] repeats in their huntingtin (or other) gene show a reduced penetrance for the disease, whereas an individual with 80 [CAG] repeats would develop juvenile HD (for review, see Nance, 1997). Both Q35-GFP and Q80-GFP formed aggregates in granule cells.…”

Section: Characteristics Of Polyglutamine-gfp Fusion Protein Aggregatmentioning

confidence: 99%

Generation of Neuronal Intranuclear Inclusions by Polyglutamine-GFP: Analysis of Inclusion Clearance and Toxicity as a Function of Polyglutamine Length

et al. 1999

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“…These include Huntington disease, spinal and bulbar muscular atrophy (Kennedy's disease), Machado-Joseph disease (SCA-3), dentatorubropallidoluysian atrophy (DRPLA), 1 and spinocerebellar ataxia types 1, 2, 6, and 7 (SCA-1, SCA-2, SCA-6, SCA-7) (4 -12). Expansion of the polyglutamine repeat in these disease proteins results in selective death of neurons in different regions of the brain.…”

mentioning

confidence: 99%

Cleavage of Atrophin-1 at Caspase Site Aspartic Acid 109 Modulates Cytotoxicity

Ellerby

Andrusiak

Wellington

et al. 1999

Journal of Biological Chemistry

103

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Dentatorubropallidoluysian atrophy (DRPLA) is one of eight autosomal dominant neurodegenerative disorders characterized by an abnormal CAG repeat expansion which results in the expression of a protein with a polyglutamine stretch of excessive length. We have reported recently that four of the gene products (huntingtin, atrophin-1 (DRPLA), ataxin-3, and androgen receptor) associated with these open reading frame triplet repeat expansions are substrates for the cysteine protease cell death executioners, the caspases. This led us to hypothesize that caspase cleavage of these proteins may represent a common step in the pathogenesis of each of these four neurodegenerative diseases. Here we present evidence that caspase cleavage of atrophin-1 modulates cytotoxicity and aggregate formation. Cleavage of atrophin-1 at Asp 109 by caspases is critical for cytotoxicity because a mutant atrophin-1 that is resistant to caspase cleavage is associated with significantly decreased toxicity. Further, the altered cellular localization within the nucleus and aggregate formation associated with the expanded form of atrophin-1 are completely suppressed by mutation of the caspase cleavage site at Asp 109 . These results provide support for the toxic fragment hypothesis whereby cleavage of atrophin-1 by caspases may be an important step in the pathogenesis of DRPLA. Therefore, inhibiting caspase cleavage of the polyglutamine-containing proteins may be a feasible therapeutic strategy to prevent cell death.

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“…Anticipation is defined as higher incidence, earlier onset, or increased severity of a disease in successive generations. The molecular mechanisms governing anticipation are largely unknown except for generational expansion of trinucleotide repeats, which have been identified in a number of genetic diseases (4)(5)(6).…”

Section: Introductionmentioning

confidence: 99%

Younger Age of Cancer Initiation Is Associated with Shorter Telomere Length in Li-Fraumeni Syndrome

et al. 2007

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Li-Fraumeni syndrome (LFS) is a cancer predisposition syndrome frequently associated with germ line TP53 mutations. Unpredictable and disparate age of cancer onset is a major challenge in the management of LFS. Genetic modifiers, including the MDM2-SNP309 polymorphism, and genetic anticipation have been suggested as plausible explanations for young age of tumor onset, but the molecular mechanisms for these observations are unknown. We speculated that telomere attrition will increase genomic instability and cause earlier tumor onset in successive generations. We analyzed mean telomere length and MDM2-SNP309 polymorphism status in individuals from multiple LFS families and controls. A total of 45 peripheral blood lymphocyte samples were analyzed from 9 LFS families and 15 controls. High rate of MDM2-SNP309 was found in TP53 carriers (P = 0.0003). In children, telomere length was shorter in carriers affected with cancer than in nonaffected carriers and wild-type controls (P < 0.0001). The same pattern was seen in adults (P = 0.002). Within each family, telomere length was shorter in children with cancer than in their nonaffected siblings and their noncarrier parents. Telomere attrition between children and adults was faster in carriers than in controls. Our results support the role of MDM2-SNP309 as a genetic modifier in LFS. The novel finding of accelerated telomere attrition in LFS suggests that telomere length could explain earlier age of onset in successive generations of the same family with identical

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Clinical Aspects of CAG Repeat Diseases

Cited by 78 publications

References 161 publications

Generation of Neuronal Intranuclear Inclusions by Polyglutamine-GFP: Analysis of Inclusion Clearance and Toxicity as a Function of Polyglutamine Length

Generation of Neuronal Intranuclear Inclusions by Polyglutamine-GFP: Analysis of Inclusion Clearance and Toxicity as a Function of Polyglutamine Length

Cleavage of Atrophin-1 at Caspase Site Aspartic Acid 109 Modulates Cytotoxicity

Younger Age of Cancer Initiation Is Associated with Shorter Telomere Length in Li-Fraumeni Syndrome

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