Abnormal gene product identified in hereditary dentatorubral–pallidoluysian atrophy (DRPLA) brain

Yazawa, Ikuru; Nukina, Nobuyuki; Hashida, Hideji; Goto, Jun; Yamada, Masao; Kanazawa, Ichiro

doi:10.1038/ng0595-99

Cited by 150 publications

(88 citation statements)

References 33 publications

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“…Although proteins containing expanded polyglutamine domains are expressed in virtually every tissue, they appear to cause cell death only in the central nervous system [16,17] and in a transiently transfected mammalian cell line [13]. In this paper we demonstrate that expression of long polyglutamine repeats (59-81 residues) in GST-fusion proteins causes lengthand concentration-dependent inhibition of cell growth in E. coli.…”

Section: Discussionmentioning

confidence: 92%

Toxicity of expanded polyglutamine‐domain proteins in Escherichia coli

et al. 1996

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Five neurodegenerative diseases are caused by proteins with expanded polyglutamine domains. Toxicity of these proteins has been previously identified only in mammals, and no simple model systems are available. In this paper, we demonstrate in E. coli that long polyglutamine domains (59-N residues) as GST-fusion proteins inhibit growth while smaller glutamine (10-35 residues) or polyalanine (61 residues) domains have no effect. Analogously in humans, polyglutamine repeats less than 3540 glutamines produce a normal phenotype, while expansion greater than 40 glutamines is always associated with disease. Expression of polyglutamine proteins in E. coli may help identify the molecular mechanism of pathogenesis of CAG trinucleotide repeat diseases and be a useful screen to identify potential therapeutic compounds.

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Section: Discussionmentioning

confidence: 92%

Toxicity of expanded polyglutamine‐domain proteins in Escherichia coli

et al. 1996

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“…It has a nuclear localization signal (NLS) in the N-terminus and a nuclear export signal (NES) in the Cterminus, which allow both nuclear and cytoplasmic localization of the protein (Yazawa et al, 1995(Yazawa et al, , 1997Okamura-Oho et al, 1999;Nucifora et al, 2003). In Drosophila, Atrophin acts as a transcription co-repressor in regulating segmentation and planar polarity during embryonic development (Zhang et al, 2002;Wang et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

C‐terminal deletion of the atrophin‐1 protein results in growth retardation but not neurodegeneration in mice

Ying

Zhuang

et al. 2009

Developmental Dynamics

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Dentatorubral-pallidoluysian atrophy (DRPLA) is a dominant hereditary neurodegenerative disorder caused by the expansion of a poly-glutamine (poly-Q) repeat in Atrophin-1 protein. Ectopic expression of a poly-Q expanded human Atrophin-1 is sufficient to induce DRPLA phenotypes in mice. However, it is still unclear whether the dominant effect of poly-Q expansion is due to the functional interference with wildtype Atrophin-1 proteins, which exist in both patients and transgenic mice. Here we report the generation and analysis of an Atrophin-1 targeting allele that expresses a truncated protein lacking both the poly-Q repeat and following C-terminal peptides. Homozygous mutants exhibit growth retardation and progressive male infertility, but no obvious signs of neurodegeneration. Moreover, the mutant allele neither blocked nor enhanced the neurodegenerative phenotypes caused by a poly-Q expanded transgene. These results support the model that poly-Q expanded Atrophin-1 proteins cause DRPLA in a manner independent of any functional interaction with wild-type Atrophin-1 proteins.

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“…Yazawa et al (1995) identified the DRPLA gene product in normal human brains as a ~ 190 kD, and in DRPLA brains as a larger ~205 kD [184].…”

Section: Paroxysmal Nocturnal Hemoglobinuria (Pnh)mentioning

confidence: 99%

Human genetics: Past, present, and future, with special reference to major trends in Japan

Yanase

1997

Jap J Human Genet

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Abnormal gene product identified in hereditary dentatorubral–pallidoluysian atrophy (DRPLA) brain

Cited by 150 publications

References 33 publications

Toxicity of expanded polyglutamine‐domain proteins in Escherichia coli

Toxicity of expanded polyglutamine‐domain proteins in Escherichia coli

C‐terminal deletion of the atrophin‐1 protein results in growth retardation but not neurodegeneration in mice

Human genetics: Past, present, and future, with special reference to major trends in Japan

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