Key Points
-
Polyglutamine disorders involve an expanded stretch of CAG trinucleotides that encodes a glutamine tract in proteins specific for each disease. The discovery of this similarity among very heterogenous disorders has pointed to a shared mechanism for the initiation of the pathogenesis, which is probably related to the ability of the mutant protein to undergo self-aggregation, forming insoluble cellular inclusions.
-
In every polyglutamine disorder, the phenotype caused by the mutant allele is dominant. In addition, each disease shows a characteristic threshold for polyglutamine length below which symptoms do not occur. Above the threshold, there is a progressive decrease in onset age with polyglutamine length.
-
The discovery of the glutamine tract as a crucial element in triggering the pathological changes has led to the development of several transgenic mouse models of the different disorders. They have been designed either to reproduce the disease phenotype by the introduction of the mutant version of the human gene or to reproduce the genotype by introducing an equivalent mutation into the endogenous locus.
-
Mice that express the polyglutamine fragments of human huntingtin tend to show cellular inclusions analogous to those described in Huntington's disease. However, these animals do not show the whole phenotypic characteristics of the human pathology as, for instance, cell death is not observed. In fact, for neuronal loss to occur, expression of the full-length mutant protein is necessary.
-
Mice that encode an enlarged glutamine tract in the endogenous huntingtin gene do not develop profound neurological signs and, similarly, the formation of cellular inclusions is subtle and progresses very slowly. Therefore, these animals may be valuable for investigating the mechanism of initiation of the disorder, but are not likely to illuminate its final stages.
-
The genetic analysis of the polyglutamine disorders indicates that the development of therapeutic strategies should focus on four main points: first, the study of the abnormal conformation of the expanded glutamine tract; second, the identification of the targets first affected by the mutant protein; third, the examination of the biochemical changes downstream from the initiating process; and last, the replacement of lost tissue through neuronal transplantation.
Abstract
Two decades ago, molecular genetic analysis provided a new approach for defining the roots of inherited disorders. This strategy has proved particularly powerful because, with only a description of the inheritance pattern, it can uncover previously unsuspected mechanisms of pathogenesis that are not implicated by known biological pathways or by the disease manifestations. Nowhere has the impact of molecular genetics been more evident than in the dominantly inherited neurodegenerative disorders, where eight unrelated diseases have been revealed to possess the same type of mutation — an expanded polyglutamine encoding sequence — affecting different genes.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$189.00 per year
only $15.75 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Goldfarb, L. G. et al. Unstable triplet repeat and phenotypic variability of spinocerebellar ataxia type 1. Ann. Neurol. 39, 500– 506 (1996).
Gusella, J. F. et al. Huntington's disease. Cold Spring Harb. Symp.Quant. Biol. 61, 615–626 ( 1996).
Ikeuchi, T. et al. Spinocerebellar ataxia type 6: CAG repeat expansion in α 1A voltage-dependent calcium channel gene and clinical variations in Japanese population. Ann. Neurol. 42, 879 –884 (1997).
Lang, A. E., Rogaeva, E. A., Tsuda, T., Hutterer, J. & St George-Hyslop, P. Homozygous inheritance of the Machado–Joseph disease gene. Ann. Neurol. 36, 443–447 (1994).
Lerer, I., Merims, D., Abeliovich, D., Zlotogora, J. & Gadoth, N. Machado–Joseph disease: correlation between the clinical features, the CAG repeat length and homozygosity for the mutation. Eur. J. Hum. Genet. 4, 3– 7 (1996).
Sanpei, K. et al. Identification of the spinocerebellar ataxia type 2 gene using a direct identification of repeat expansion and cloning technique, DIRECT . Nature Genet. 14, 277– 284 (1996).
Sato, K. et al. Does homozygosity advance the onset of dentatorubral-pallidoluysian atrophy? Neurology 45, 1934– 1936 (1995).
Sobue, G. et al. Homozygosity for Machado–Joseph disease gene enhances phenotypic severity. J. Neurol. Neurosurg. Psychiat. 60, 354–356 (1996).
Takiyama, Y. et al. A Japanese family with spinocerebellar ataxia type 6 which includes three individuals homozygous for an expanded CAG repeat in the SCA6/CACNL1A4 gene. J. Neurol. Sci. 158, 141– 147 (1998).
Matsuyama, Z. et al. Molecular features of the CAG repeats of spinocerebellar ataxia 6 (SCA6). Hum. Mol. Genet. 6, 1283– 1287 (1997).
Kato, T. et al. Sisters homozygous for the spinocerebellar ataxia type 6 (SCA6)/CACNA1A gene associated with different clinical phenotypes. Clin. Genet. 58, 69–73 ( 2000).Whereas onset of neurological symptoms in two sisters homozygous for SCA6 mutant alleles was identical, disease progression and symptoms varied significantly, supporting a role for genetic, environmental or stochastic modifiers.
Vonsattel, J. P. Neuropathology of Huntington's disease. Neurosci. News 3, 45–48 (2000).
Furtado, S. et al. Relationship between trinucleotide repeats and neuropathological changes in Huntington's disease. Ann. Neurol. 39, 132–136 (1996).
Penney, J. B. Jr, Vonsattel, J. P., MacDonald, M. E., Gusella, J. F. & Myers, R. H. CAG repeat number governs the development rate of pathology in Huntington's disease. Ann. Neurol. 41, 689– 692 (1997).
Gusella, J. F., Persichetti, F. & MacDonald, M. E. The genetic defect causing Huntington's disease: repeated in other contexts? Mol. Med. 3, 238–246 (1997).
Kieburtz, K. et al. Trinucleotide repeat length and progression of illness in Huntington's disease. J. Med. Genet. 31, 872–874 (1994).
Scherzinger, E. et al. Huntingtin-encoded polyglutamine expansions form amyloid-like protein aggregates in vitro and in vivo. Cell 90, 549–558 (1997).
Huang, C. C. et al. Amyloid formation by mutant huntingtin: threshold, progressivity and recruitment of normal polyglutamine proteins. Somat. Cell. Mol. Genet. 24, 217–233 (1998).The aggregation process predicted by Perutz et al.19 and demonstrated by Scherzinger et al.17 fulfils the genetic criteria for involvement in the initiation of pathogenesis, indicating that it can be used as a measure of the pathogenic conformational property of mutant huntingtin.
Perutz, M. F., Johnson, T., Suzuki, M. & Finch, J. T. Glutamine repeats as polar zippers: their possible role in inherited neurodegenerative diseases. Proc. Natl Acad. Sci. USA 91, 5355– 5358 (1994).
Grunewald, T. & Beal, M. F. Bioenergetics in Huntington's disease . Ann. NY Acad. Sci. 893, 203– 213 (1999).
Narain, Y., Wyttenbach, A., Rankin, J., Furlong, R. A. & Rubinsztein, D. C. A molecular investigation of true dominance in Huntington's disease. J. Med. Genet. 36, 739–746 (1999).
Mangiarini, L. et al. Exon 1 of the HD gene with an expanded CAG repeat is sufficient to cause a progressive neurological phenotype in transgenic mice. Cell 87, 493–506 ( 1996).
Hackam, A. S. et al. The influence of huntingtin protein size on nuclear localization and cellular toxicity. J. Cell Biol. 141, 1097–1105 (1998).
Kuemmerle, S. et al. Huntington aggregates may not predict neuronal death in Huntington's disease. Ann. Neurol. 46, 842– 849 (1999).
Klement, I. A. et al. Ataxin-1 nuclear localization and aggregation: role in polyglutamine-induced disease in SCA1 transgenic mice Cell 95, 41–53 (1998).A clear demonstration that formation of inclusions does not correlate with cell death in a transgenic model with overt neuronal loss.
Lunkes, A. & Mandel, J. L. A cellular model that recapitulates major pathogenic steps of Huntington's disease. Hum. Mol. Genet. 7, 1355–1361 ( 1998).
Persichetti, F. et al. Mutant huntingtin forms in vivo complexes with distinct context-dependent conformations of the polyglutamine segment. Neurobiol. Dis. 6, 364–375 (1999).The polyglutamine segment of huntingtin shows different conformations when present in an amino-terminal fragment or in the full-length protein, and both conformations may be found in different morphological inclusions.
Saudou, F., Finkbeiner, S., Devys, D. & Greenberg, M. E. Huntingtin acts in the nucleus to induce apoptosis but death does not correlate with the formation of intranuclear inclusions. Cell 95, 55–66 (1998).
Cooper, J. K. et al. Truncated N-terminal fragments of huntingtin with expanded glutamine repeats form nuclear and cytoplasmic aggregates in cell culture . Hum. Mol. Genet. 7, 783– 790 (1998).
Kim, M. et al. Mutant huntingtin expression in clonal striatal cells: dissociation of inclusion formation and neuronal survival by caspase inhibition. J. Neurosci. 19, 964–973 (1999).
Sato, A. et al. Adenovirus-mediated expression of mutant DRPLA proteins with expanded polyglutamine stretches in neuronally differentiated PC12 cells. Preferential intranuclear aggregate formation and apoptosis. Hum. Mol. Genet. 8, 997–1006 (1999).
Simeoni, S. et al. Motoneuronal cell death is not correlated with aggregate formation of androgen receptors containing an elongated polyglutamine tract. Hum. Mol. Genet. 9, 133–144 (2000).
Cummings, C. J. et al. Chaperone suppression of aggregation and altered subcellular proteasome localization imply protein misfolding in SCA1. Nature Genet. 19, 148–154 ( 1998).
Cummings, C. J. et al. Mutation of the E6-AP ubiquitin ligase reduces nuclear inclusion frequency while accelerating polyglutamine-induced pathology in SCA1 mice . Neuron 24, 879–892 (1999).
Chai, Y., Koppenhafer, S. L., Shoesmith, S. J., Perez, M. K. & Paulson, H. L. Evidence for proteasome involvement in polyglutamine disease: localization to nuclear inclusions in SCA3/MJD and suppression of polyglutamine aggregation in vitro. Hum. Mol. Genet. 8, 673–682 ( 1999).
Stenoien, D. L. et al. Polyglutamine-expanded androgen receptors form aggregates that sequester heat shock proteins, proteasome components and SRC-1, and are suppressed by the HDJ-2 chaperone. Hum. Mol. Genet. 8, 731–741 (1999).
Wyttenbach, A. et al. Effects of heat shock, heat shock protein 40 (HDJ-2), and proteasome inhibition on protein aggregation in cellular models of Huntington's disease. Proc. Natl Acad. Sci. USA 97, 2898 –2903 (2000).
Davies, S. W. et al. Formation of neuronal intranuclear inclusions underlies the neurological dysfunction in mice transgenic for the HD mutation. Cell 90, 537–548 ( 1997).This paper first showed the aggregation-promoting property of a mutant amino-terminal huntingtin fragment in a transgenic mouse and caused a reappraisal of human Huntington's disease neuropathology by DiFiglia and colleagues41.
Hurlbert, M. S. et al. Mice transgenic for an expanded CAG repeat in the Huntington's disease gene develop diabetes. Diabetes 48, 649–651 (1999).
Yamamoto, A., Lucas, J. J. & Hen, R. Reversal of neuropathology and motor dysfunction in a conditional model of Huntington's disease. Cell 101 , 57–66 (2000). A repressible Huntington's disease exon 1 transgenic mouse model showed that eliminating the continued production of the mutant fragment causes nuclear inclusions to disappear, indicating that they are dynamic structures metabolized by the neuron.
DiFiglia, M. et al. Aggregation of huntingtin in neuronal intranuclear inclusions and dystrophic neurites in brain. Science 277, 1990–1993 (1997).
Rubinsztein, D. C., Wyttenbach, A. & Rankin, J. Intracellular inclusions, pathological markers in diseases caused by expanded polyglutamine tracts? J. Med. Genet. 36, 265–270 (1999).
Burright, E. N. et al. SCA1 transgenic mice: a model for neurodegeneration caused by an expanded CAG trinucleotide repeat. Cell 82, 937–948 (1995).
Bingham, P. M. et al. Stability of an expanded trinucleotide repeat in the androgen receptor gene in transgenic mice. Nature Genet. 9, 191–196 (1995).
Ikeda, H. et al. Expanded polyglutamine in the Machado–Joseph disease protein induces cell death in vitro and in vivo. Nature Genet. 13, 196–202 ( 1996).
Schilling, G. et al. Nuclear accumulation of truncated atrophin-1 fragments in a transgenic mouse model of DRPLA. Neuron 24, 275–286 (1999).
Sato, T. et al. Transgenic mice harboring a full-length human mutant DRPLA gene exhibit age-dependent intergenerational and somatic instabilities of CAG repeats comparable with those in DRPLA patients. Hum. Mol. Genet. 8, 99–106 (1999).
Reddy, P. H. et al. Behavioural abnormalities and selective neuronal loss in HD transgenic mice expressing mutated full-length HD cDNA. Nature Genet. 20, 198–202 ( 1998).
Hodgson, J. G. et al. A YAC mouse model for Huntington's disease with full-length mutant huntingtin, cytoplasmic toxicity, and selective striatal neurodegeneration . Neuron 23, 181–192 (1999).
Lorenzetti, D. et al. Repeat instability and motor incoordination in mice with a targeted expanded CAG repeat in the Sca1 locus. Hum. Mol. Genet. 9, 779–785 ( 2000).
Wheeler, V. C. et al. Length-dependent gametic CAG repeat instability in the Huntington's disease knock-in mouse. Hum. Mol. Genet. 8, 115–122 (1999).
Shelbourne, P. F. et al. A Huntington's disease CAG expansion at the murine Hdh locus is unstable and associated with behavioural abnormalities in mice. Hum. Mol. Genet. 8, 763–774 (1999).
Levine, M. S. et al. Enhanced sensitivity to N-methyl-d-aspartate receptor activation in transgenic and knockin mouse models of Huntington's disease. J. Neurosci. Res. 58, 515– 532 (1999).
Usdin, M. T., Shelbourne, P. F., Myers, R. M. & Madison, D. V. Impaired synaptic plasticity in mice carrying the Huntington's disease mutation . Hum. Mol. Genet. 8, 839– 846 (1999).
Menalled, L. et al. Decrease in striatal enkephalin mRNA in mouse models of Huntington's disease. Exp. Neurol. 162, 328– 342 (2000).
Wheeler, V. C. et al. Long glutamine tracts cause nuclear localization of a novel form of huntingtin in medium spiny striatal neurons in HdhQ92 and HdhQ111 knock-in mice. Hum. Mol. Genet. 9, 503– 513 (2000).Huntington's disease knock-in mutant mice are shown to display a phenotype of the full-length mutant protein that fulfils the genetic criteria for involvement in initiating pathogenesis.
Nance, M. A., Mathias-Hagen, V., Breningstall, G., Wick, M. J. & McGlennen, R. C. Analysis of a very large trinucleotide repeat in a patient with juvenile Huntington's disease. Neurology 52, 392–394 ( 1999).A CAG repeat longer than all those used in transgenic mice so far is shown to cause Huntington's disease in humans with onset only after 2.5 years and a disease course of more than a decade.
Heiser, V. et al. Inhibition of huntingtin fibrillogenesis by specific antibodies and small molecules: implications for Huntington's disease therapy. Proc. Natl Acad. Sci. USA 97, 6739– 6744 (2000).
Nagai, Y. et al. Inhibition of polyglutamine protein aggregation and cell death by novel peptides identified by phage display screening. J. Biol. Chem. 275, 10437–10442 ( 2000).References 58 and 59 show the potential for the identification of small molecules and peptides that interfere with polyglutamine aggregation, which may lead to new therapeutic agents.
Wellington, C. L. & Hayden, M. R. Caspases and neurodegeneration: on the cutting edge of new therapeutic approaches. Clin. Genet. 57, 1–10 ( 2000).
Satyal, S. H. et al. Polyglutamine aggregates alter protein folding homeostasis in Caenorhabditis elegans. Proc. Natl Acad. Sci. USA 97, 5750–5755 (2000).
Kobayashi, Y. et al. Chaperones Hsp70 and Hsp40 suppress aggregate formation and apoptosis in cultured neuronal cells expressing truncated androgen receptor protein with expanded polyglutamine tract. J. Biol. Chem. 275, 8772–8778 (2000).
Krobitsch, S. & Lindquist, S. Aggregation of huntingtin in yeast varies with the length of the polyglutamine expansion and the expression of chaperone proteins. Proc. Natl Acad. Sci. USA 97, 1589–1594 (2000).
Kazemi-Esfarjani, P. & Benzer, S. Genetic suppression of polyglutamine toxicity in Drosophila. Science 287, 1837–1840 (2000).
Warrick, J. M. et al. Suppression of polyglutamine-mediated neurodegeneration in Drosophila by the molecular chaperone HSP70. Nature Genet. 23, 425–428 ( 1999).
Muchowski, P. J. et al. Hsp70 and Hsp40 chaperones can inhibit self-assembly of polyglutamine proteins into amyloid-like fibrils. Proc. Natl Acad. Sci. USA 97, 7841–7846 (2000).
Bachoud-Levi, A. et al. Safety and tolerability assessment of intrastriatal neural allografts in five patients with Huntington's disease. Exp. Neurol. 161, 194–202 ( 2000).
Magavi, S. S., Leavitt, B. R. & Macklis, J. D. Induction of neurogenesis in the neocortex of adult mice. Nature 405, 951–955 (2000).
van Dellen, A., Blakemore, C., Deacon, R., York, D. & Hannan, A. J. Delaying the onset of Huntington's in mice. Nature 404, 721– 722 (2000).A significant improvement in the health and motor function of transgenic mice expressing exon 1 of the human HD gene, with no corresponding decrease in nuclear inclusion formation, can be achieved by enriching their environment with cardboard, paper and plastic objects.
Ona, V. O. et al. Inhibition of caspase-1 slows disease progression in a mouse model of Huntington's disease. Nature 399, 263–267 (1999).
Ferrante, R. J. et al. Neuroprotective effects of creatine in a transgenic mouse model of Huntington's disease. J. Neurosci. 20, 4389–4397 (2000).
Chen, M. et al. Minocycline inhibits caspase-1 and caspase-3 expression and delays mortality in a transgenic mouse model of Huntington disease. Nature Med. 6, 797–801 ( 2000).
Jackson, G. R. et al. Polyglutamine-expanded human huntingtin transgenes induce degeneration of Drosophila photoreceptor neurons. Neuron 21, 633–642 ( 1998).
Warrick, J. M. et al. Expanded polyglutamine protein forms nuclear inclusions and causes neural degeneration in Drosophila. Cell 93, 939–949 (1998).
Faber, P. W., Alter, J. R., MacDonald, M. E. & Hart, A. C. Polyglutamine-mediated dysfunction and apoptotic death of a Caenorhabditis elegans sensory neuron. Proc. Natl Acad. Sci. USA 96, 179–184 (1999).
Marsh, J. L. et al. Expanded polyglutamine peptides alone are intrinsically cytotoxic and cause neurodegeneration in Drosophila. Hum. Mol. Genet. 9, 13–25 (2000 ).In a Drosophila model, polyglutamine is neurotoxic, but its toxicity can be modified by attaching it to non-polyglutamine peptides or by embedding it in a protein, demonstrating the context-specificity of the pathogenic effect.
Rubinsztein, D. C. et al. Genotypes at the GluR6 kainate receptor locus are associated with variation in the age of onset of Huntington disease. Proc. Natl Acad. Sci. USA 94, 3872–3876 (1997).This paper identifies the first genetic factor other than the disease gene that modifies the onset of a polyglutamine disorder, confirmed in a different population by MacDonald and colleagues78.
MacDonald, M. E. et al. Evidence for the GluR6 gene associated with younger onset age of Huntington's disease. Neurology 53, 1330–1332 (1999).
Farrer, L. A. et al. The normal Huntington disease (HD) allele, or a closely linked gene, influences age at onset of HD. Am. J. Hum. Genet. 53, 125–130 (1993).
DeStefano, A. L. et al. A familial factor independent of CAG repeat length influences age at onset of Machado–Joseph disease. Am. J. Hum. Genet. 59, 119–127 ( 1996).
Ranum, L. P. et al. Molecular and clinical correlations in spinocerebellar ataxia type I: evidence for familial effects on the age at onset. Am. J. Hum. Genet. 55, 244–252 (1994).
Shizuka, M. et al. Spinocerebellar ataxia type 6: CAG trinucleotide expansion, clinical characteristics and sperm analysis. Eur. J. Neurol. 5, 381–387 (1998).
Schols, L. et al. Spinocerebellar ataxia type 6: genotype and phenotype in German kindreds. J. Neurol. Neurosurg. Psychiatry 64, 67–73 (1998).
Nagai, Y. et al. Clinical and molecular genetic study in seven Japanese families with spinocerebellar ataxia type 6. J. Neurol. Sci. 157, 52–59 (1998).
Matsumura, R. et al. Spinocerebellar ataxia type 6. Molecular and clinical features of 35 Japanese patients including one homozygous for the CAG repeat expansion . Neurology 49, 1238–1243 (1997).
Kim, J. M. et al. Spinocerebellar ataxia type 2 in seven Korean families: CAG trinucleotide expansion and clinical characteristics. J. Korean Med. Sci. 14, 659–664 ( 1999).
Gouw, L. G. et al. Analysis of the dynamic mutation in the SCA7 gene shows marked parental effects on CAG repeat transmission. Hum. Mol. Genet. 7, 525–532 (1998).
David, G. et al. Molecular and clinical correlations in autosomal dominant cerebellar ataxia with progressive macular dystrophy (SCA7). Hum. Mol. Genet. 7, 165–170 ( 1998).
Johansson, J. et al. Expanded CAG repeats in Swedish spinocerebellar ataxia type 7 (SCA7) patients: effect of CAG repeat length on the clinical manifestation . Hum. Mol. Genet. 7, 171– 176 (1998).
Benton, C. S. et al. Molecular and clinical studies in SCA-7 define a broad clinical spectrum and the infantile phenotype. Neurology 51, 1081–1086 (1998).
Giunti, P. et al. Molecular and clinical study of 18 families with ADCA type II: evidence for genetic heterogeneity and de novo mutation. Am. J. Hum. Genet. 64, 1594–1603 (1999).
Martin, J., Van Regemorter, N., Del-Favero, J., Lofgren, A. & Van Broeckhoven, C. Spinocerebellar ataxia type 7 (SCA7) — correlations between phenotype and genotype in one large Belgian family. J. Neurol. Sci. 168, 37– 46 (1999).
Igarashi, S. et al. Strong correlation between the number of CAG repeats in androgen receptor genes and the clinical onset of features of spinal and bulbar muscular atrophy. Neurology 42, 2300– 2302 (1992).
La Spada, A. R. et al. Meiotic stability and genotype-phenotype correlation of the trinucleotide repeat in X-linked spinal and bulbar muscular atrophy. Nature Genet. 2, 301–304 (1992).
Shimada, N. et al. X-linked recessive bulbospinal neuronopathy: clinical phenotypes and CAG repeat size in androgen receptor gene. Muscle Nerve 18, 1378–1384 (1995).
Filla, A. et al. Spinocerebellar ataxia type 2 in southern Italy: a clinical and molecular study of 30 families. J. Neurol. 246, 467–471 (1999).
Moseley, M. L. et al. Incidence of dominant spinocerebellar and Friedreich triplet repeats among 361 ataxia families. Neurology 51, 1666–1671 (1998).
Riess, O. et al. SCA2 trinucleotide expansion in German SCA patients. Neurogenetics 1, 59–64 ( 1997).
Acknowledgements
The authors thank J.-P. Vonsattel for his contribution. Their work is supported by the Huntington's Disease Society of America Coallition for the Cure, the Hereditary Disease Foundation and NIH.
Author information
Authors and Affiliations
Glossary
- SPINAL AND BULBAR MUSCULAR ATROPHY
-
Disorder characterized by progressive weakness and wasting of mouth, throat and skeletal muscles, which tends to affect only men.
- POLYMORPHISM
-
The simultaneous existence in the same population of two or more forms (alleles) of a DNA sequence with a frequency that is greater than 1%.
- MEDIUM SPINY NEURONS
-
Cell population that constitutes the main striatal inhibitory output to the globus pallidus.
- SPINOCEREBELLAR ATAXIA
-
Disorder characterized by progressive cerebellar atrophy, which leads to gait ataxia and incoordination.
- CHOREOATHETOSIS
-
Movement disorder characterized by constant writhing and jerking motion.
- SDS–PAGE
-
Sodium dodecyl sulphate-polyacrylamide gel electrophoresis. A method for resolving a multimeric protein into its subunits and determining their separate molecular weights.
- AMYLOID FIBRES
-
Insoluble, relatively inert fibres that are resistant to proteolysis, made from proteins in a β-pleated structure.
- PROTEASOME
-
Protein complex responsible for degrading intracellular proteins that have been tagged for destruction by the addition of ubiquitin.
- YEAST ARTIFICIAL CHROMOSOME
-
A cloning vector capable of propagation in yeast, where it functions as an artificial chromosome.
- CASPASES
-
Cysteine proteases involved in apoptosis, which cleave at specific aspartate residues.
- DOMINANT-NEGATIVE
-
A mutant protein that reduces the activity of the wild-type form.
- MINOCYCLINE
-
An antibiotic that belongs to the tetracycline group.
Rights and permissions
About this article
Cite this article
Gusella, J., MacDonald, M. Molecular genetics: Unmasking polyglutamine triggers in neurodegenerative disease. Nat Rev Neurosci 1, 109–115 (2000). https://doi.org/10.1038/35039051
Issue Date:
DOI: https://doi.org/10.1038/35039051
This article is cited by
-
Neurodegenerative diseases: a hotbed for splicing defects and the potential therapies
Translational Neurodegeneration (2021)
-
Post-symptomatic Delivery of Brain-Derived Neurotrophic Factor (BDNF) Ameliorates Spinocerebellar Ataxia Type 1 (SCA1) Pathogenesis
The Cerebellum (2021)
-
CHIP as a therapeutic target for neurological diseases
Cell Death & Disease (2020)
-
A slipped-CAG DNA-binding small molecule induces trinucleotide-repeat contractions in vivo
Nature Genetics (2020)
-
Characterization of the human head louse nit sheath reveals proteins with adhesive property that show no resemblance to known proteins
Scientific Reports (2019)