Pathogenesis of Polyglutamine Diseases


Polyglutamine (polyQ) diseases are neurodegenerative disorders caused by expansion in specific genes of a trinucleotide repeat, cytosine–adenine–guanine (CAG), which encodes glutamine. In 1991, CAG repeat expansion in the androgen receptor was linked to spinal and bulbar muscular atrophy (SBMA), thus indicating for the first time a causative role of polyQ expansion in neurodegenerative disorders. Subsequently, polyQ expansions in eight other genes were shown to be responsible for different neurodegenerative diseases, including Huntington disease, dentatorubral‐pallidoluysian atrophy and six types of spinocerebellar ataxia. PolyQ diseases share several features, such as the phenomenon of genetic anticipation, and that to be late‐onset and progressive disorders. Despite these and other common features, specific populations of neurons are vulnerable in each disease. Approximately 20 years after the discovery of expanded polyQ as a leading cause of neurodegeneration, why selective neuronal populations degenerate in each disorder is still an enigma.

Key Concepts:

  • Polyglutamine diseases are a family of late onset, genetically inherited neurodegenerative disorders.

  • Polyglutamine diseases are caused by expansion of the CAG trinucleotide repeat encoding glutamine in nine different genes.

  • Expansion of polyglutamine confers a novel, toxic gain of function to the mutant protein.

  • The length of the polyglutamine tract correlates with disease onset and dictates disease severity.

  • Polyglutamine proteins are ubiquitous. None the less, expansion of polyglutamine tracts causes selective neuronal dysfunction and degeneration.

  • Specific populations of neurons degenerate in each polyglutamine disease, giving rise to different clinical disease manifestations.

Keywords: polyglutamine disease; neurodegeneration; gain and loss of function; aggregate/inclusions; Huntington disease; spinocerebellar ataxia; Kennedy disease; dentatorubral‐pallidoluysian atrophy

Figure 1.

Polyglutamine (polyQ) diseases. PolyQ diseases are a family of nine neurodegenerative disorders, which includes Huntington disease (HD), dentatorubral‐pallidoluysian atrophy (DRPLA), spinal and bulbar muscular atrophy (SBMA) and six types of spinocerebellar ataxia (SCA). Although polyQ diseases are caused by the same mutation, expansion of a polyQ tract in the coding region of nine different genes, specific populations of neurons degenerate in each disease, such as striatal and cortical neurons in HD, dentate nucleus of the cerebellum and pallidum in DRPLA, lower motor neurons in SBMA and Purkinje cells in SCAs.

Figure 2.

Pathogenic pathways in polyglutamine (polyQ) diseases. PolyQ expansion affects several cellular processes. PolyQ proteins accumulate in the nucleus and alter gene expression. PolyQ proteins alter mitochondrial function and cell metabolism. PolyQ proteins are degraded by the ubiquitin‐proteasome system and autophagy. Interaction of the polyQ proteins with the cellular protein degradation machinery may hamper its function, thereby altering cellular homeostasis. PolyQ proteins are not properly folded and accumulate in the cells in forms of aggregates and inclusions. PolyQ proteins alter fast axonal transport and synaptic transmission.



Arrasate M, Mitra S, Schweitzer ES, Segal MR and Finkbeiner S (2004) Inclusion body formation reduces levels of mutant huntingtin and the risk of neuronal death. Nature 431: 805–810.

Bence NF, Sampat RM and Kopito RR (2001) Impairment of the ubiquitin‐proteasome system by protein aggregation. Science 292: 1552–1555.

Cui L, Jeong H, Borovecki F et al. (2006) Transcriptional repression of PGC‐1alpha by mutant huntingtin leads to mitochondrial dysfunction and neurodegeneration. Cell 127: 59–69.

Custer SK, Garden GA, Gill N et al. (2006) Bergmann glia expression of polyglutamine‐expanded ataxin‐7 produces neurodegeneration by impairing glutamate transport. Nature Neuroscience 9: 1302–1311.

David G, Abbas N, Stevanin G et al. (1997) Cloning of the SCA7 gene reveals a highly unstable CAG repeat expansion. Nature Genetics 17: 65–70.

Dragatsis I, Levine MS and Zeitlin S (2000) Inactivation of Hdh in the brain and testis results in progressive neurodegeneration and sterility in mice. Nature Genetics 26: 300–306.

Duyao MP, Auerbach AB, Ryan A et al. (1995) Inactivation of the mouse Huntington's disease gene homolog Hdh. Science 269: 407–410.

Ellerby LM, Hackam AS, Propp SS et al. (1999) Kennedy's disease: caspase cleavage of the androgen receptor is a crucial event in cytotoxicity. Journal of Neurochemistry 72: 185–195.

Evert BO, Vogt IR, Vieira‐Saecker AM et al. (2003) Gene expression profiling in ataxin‐3 expressing cell lines reveals distinct effects of normal and mutant ataxin‐3. Journal of Neuropathology and Experimental Neurology 62: 1006–1018.

Gauthier LR, Charrin BC, Borrell‐Pages M et al. (2004) Huntingtin controls neurotrophic support and survival of neurons by enhancing BDNF vesicular transport along microtubules. Cell 118: 127–138.

Huntington G (1872) On Chorea. Medical and Surgical Reporter 26: 317–321.

Imbert G, Saudou F, Yvert G et al. (1996) Cloning of the gene for spinocerebellar ataxia 2 reveals a locus with high sensitivity to expanded CAG/glutamine repeats. Nature Genetics 14: 285–291.

Kawaguchi Y, Okamoto T, Taniwaki M et al. (1994) CAG expansions in a novel gene for Machado‐Joseph disease at chromosome 14q32.1. Nature Genetics 8: 221–228.

Kawahara H (1897) A family of progressive bulbar palsy. The Journal of the Aichi Medical University Association 16: 3–4.

Kennedy WR, Alter M and Sung JH (1968) Progressive proximal spinal and bulbar muscular atrophy of late onset. A sex‐linked recessive trait. Neurology 18: 671–680.

Kiehl TR, Nechiporuk A, Figueroa KP et al. (2006) Generation and characterization of Sca2 (ataxin‐2) knockout mice. Biochemical and Biophysical Research Communications 339: 17–24.

Klement IA, Skinner PJ, Kaytor MD et al. (1998) Ataxin‐1 nuclear localization and aggregation: role in polyglutamine‐induced disease in SCA1 transgenic mice. Cell 95: 41–53.

Knight SP, Richardson MM, Osmand AP, Stakkestad A and Potter NT (1997) Expression and distribution of the dentatorubral‐pallidoluysian atrophy gene product (atrophin‐1/drplap) in neuronal and non‐neuronal tissues. Journal of the Neurological Sciences 146: 19–26.

Koide R, Ikeuchi T, Onodera O et al. (1994) Unstable expansion of CAG repeat in hereditary dentatorubral‐pallidoluysian atrophy (DRPLA). Nature Genetics 6: 9–13.

La Spada AR, Wilson EM, Lubahn DB, Harding AE and Fischbeck KH (1991) Androgen receptor gene mutations in X‐linked spinal and bulbar muscular atrophy. Nature 352: 77–79.

Li SH, McInnis MG, Margolis RL, Antonarakis SE and Ross CA (1993) Novel triplet repeat containing genes in human brain: cloning, expression, and length polymorphisms. Genomics 16: 572–579.

Lim J, Crespo‐Barreto J, Jafar‐Nejad P et al. (2008) Opposing effects of polyglutamine expansion on native protein complexes contribute to SCA1. Nature 452: 713–718.

Macdonald ME, Ambrose CM, Duyao MP et al. (1993) A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntingtons‐disease chromosomes. Cell 72: 971–983.

Matilla A, Roberson ED, Banfi S et al. (1998) Mice lacking ataxin‐1 display learning deficits and decreased hippocampal paired‐pulse facilitation. Journal of Neuroscience 18: 5508–5516.

Menzel P (1891) Beitrage zur Kenntnis der hereditaren Ataxie und Kleinhirnatrophie. Archiv fur Psychiatrie und Nervenkrankheiten 22: 160–190.

Nagafuchi S, Yanagisawa H, Sato K et al. (1994) Dentatorubral and pallidoluysian atrophy expansion of an unstable CAG trinucleotide on chromosome 12p. Nature Genetics 6: 14–18.

Nakamura K, Jeong SY, Uchihara T et al. (2001) SCA17, a novel autosomal dominant cerebellar ataxia caused by an expanded polyglutamine in TATA‐binding protein. Human Molecular Genetics 10: 1441–1448.

Nakano KK, Dawson DM and Spence A (1972) Machado disease. A hereditary ataxia in Portuguese emigrants to Massachusetts. Neurology 22: 49–55.

Nasir J, Floresco SB, O'Kusky JR et al. (1995) Targeted disruption of the Huntington's disease gene results in embryonic lethality and behavioral and morphological changes in heterozygotes. Cell 81: 811–823.

Nucifora FC Jr, Sasaki M, Peters MF et al. (2001) Interference by huntingtin and atrophin‐1 with cbp‐mediated transcription leading to cellular toxicity. Science 291: 2423–2428.

Ordway JM, Tallaksen‐Greene S, Gutekunst CA et al. (1997) Ectopically expressed CAG repeats cause intranuclear inclusions and a progressive late onset neurological phenotype in the mouse. Cell 91: 753–763.

Orr HT, Chung MY, Banfi S et al. (1993) Expansion of an unstable trinucleotide CAG repeat in spinocerebellar ataxia type 1. Nature Genetics 4: 221–226.

Perutz MF, Johnson T, Suzuki M and Finch JT (1994) Glutamine repeats as polar zippers: their possible role in inherited neurodegenerative diseases. Proceedings of the National Academy of Sciences of the USA 91: 5355–5358.

Ranganathan S, Harmison GG, Meyertholen K et al. (2009) Mitochondrial abnormalities in spinal and bulbar muscular atrophy. Human Molecular Genetics 18: 27–42.

Saudou F, Finkbeiner S, Devys D and Greenberg ME (1998) Huntingtin acts in the nucleus to induce apoptosis but death does not correlate with the formation of intranuclear inclusions. Cell 95: 55–66.

Sawa A, Wiegand GW, Cooper J et al. (1999) Increased apoptosis of Huntington disease lymphoblasts associated with repeat length‐dependent mitochondrial depolarization. Nature Medicine 5: 1194–1198.

Schmidt BJ, Greenberg CR, Allingham‐Hawkins DJ and Spriggs EL (2002) Expression of X‐linked bulbospinal muscular atrophy (Kennedy disease) in two homozygous women. Neurology 59: 770–772.

Schmitt I, Linden M, Khazneh H et al. (2007) Inactivation of the mouse Atxn3 (ataxin‐3) gene increases protein ubiquitination. Biochemical and Biophysical Research Communications 362: 734–739.

Servadio A, Koshy B, Armstrong D et al. (1995) Expression analysis of the ataxin‐1 protein in tissues from normal and spinocerebellar ataxia type 1 individuals. Nature Genetics 10: 94–98.

Shen Y, Lee G, Choe Y, Zoltewicz JS and Peterson AS (2007) Functional architecture of atrophins. Journal of Biological Chemistry 282: 5037–5044.

Smith JK, Gonda VE and Malamud N (1958) Unusual form of cerebellar ataxia; combined dentato‐rubral and pallido‐Luysian degeneration. Neurology 8: 205–209.

Smith R, Brundin P and Li JY (2005) Synaptic dysfunction in Huntington's disease: a new perspective. Cellular and Molecular Life Sciences 62: 1901–1912.

Szebenyi G, Morfini GA, Babcock A et al. (2003) Neuropathogenic forms of huntingtin and androgen receptor inhibit fast axonal transport. Neuron 40: 41–52.

Titica J and Van Bogaert L (1946) Heredo‐degenerative hemiballismus; a contribution to the question of primary atrophy of the corpus luysii. Brain 69: 251–263.

Wadia NH and Swami RK (1971) A new form of heredo‐familial spinocerebellar degeneration with slow eye movements (nine families). Brain 94: 359–374.

Wang L, Rajan H, Pitman JL, McKeown M and Tsai CC (2006) Histone deacetylase‐associating Atrophin proteins are nuclear receptor corepressors. Genes & Development 20: 525–530.

Wellington CL, Ellerby LM, Hackam AS et al. (1998) Caspase cleavage of gene products associated with triplet expansion disorders generates truncated fragments containing the polyglutamine tract. Journal of Biological Chemistry 273: 9158–9167.

Zhong X and Pittman RN (2006) Ataxin‐3 binds VCP/p97 and regulates retrotranslocation of ERAD substrates. Human Molecular Genetics 15: 2409–2420.

Zhuchenko O, Bailey J, Bonnen P et al. (1997) Autosomal dominant cerebellar ataxia (SCA6) associated with small polyglutamine expansions in the alpha 1A‐voltage‐dependent calcium channel. Nature Genetics 15: 62–69.

Zuccato C, Tartari M, Crotti A et al. (2003) Huntingtin interacts with REST/NRSF to modulate the transcription of NRSE‐controlled neuronal genes. Nature Genetics 35: 76–83.

Further Reading

Di Prospero NA and Fischbeck KH (2005) Therapeutics development for triplet repeat expansion diseases. Nature Reviews. Genetics 6(10): 756–765.

Gidalevitz T, Ben‐Zvi A, Ho KH, Brignull HR and Morimoto RI (2006) Progressive disruption of cellular protein folding in models of polyglutamine diseases. Science 311(5766): 1471–1474.

Orr HT and Zoghbi HY (2007) Trinucleotide repeat disorders. Annual Review of Neuroscience 30: 575–621.

Pennuto M and Fischbeck K (2010) Therapeutic prospects for polyglutamine disease. In: Dobson CM and Ramirez‐Alvarado M (ed.) Protein Misfolding Diseases: Current and Emerging Principles, pp. 887–902. Hoboken: Wiley.

Ross CA and Poirier MA (2004) Protein aggregation and neurodegenerative disease. Nature Medicine 10(suppl): S10–S17.

Williams AJ and Paulson HL (2008) Polyglutamine neurodegeneration: protein misfolding revisited. Trends in Neuroscience 31(10): 521–528.

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Pennuto, Maria, and Sambataro, Fabio(Dec 2010) Pathogenesis of Polyglutamine Diseases. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0021486]