Cell cycle arrest enhances the in vitro cellular toxicity of the truncated Machado-Joseph disease gene product with an expanded polyglutamine stretch

Yoshizawa, Toshihiro; Yamagishi, Yasuaki; Koseki, Naoteru; Goto, Jun; Yoshida, Hiroyuki; Shibasaki, Futoshi; Shoji, Shin’ichi; Kanazawa, Ichiro

doi:10.1093/hmg/9.1.69

Cited by 63 publications

(41 citation statements)

References 39 publications

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“…Previous reports indicated that a C-terminal portion of mutant ataxin-3 mjd1a containing the polyglutamine expansion was cytotoxic, whereas the full-length form was not (Ikeda et al, 1996;Paulson et al, 1997b;Warrick et al, 1998;Yoshizawa et al, 2000). Thus, we determined whether the putative-cleavage fragment that we detected in brain corresponded to a C-terminal portion of mutant ataxin-3 mjd1a containing the polyglutamine expansion.…”

Section: Composition Of the Mutant Ataxin-3 Putative-cleavage Fragmentmentioning

confidence: 85%

“…Previous work using transgenic animals and transfected cells demonstrated that neuronal toxicity is caused by mutant ataxin-3 mjd1a truncations, to include the polyglutamine expansion, but not the full-length protein (Ikeda et al, 1996;Paulson et al, 1997b;Warrick et al, 1998;Yoshizawa et al, 2000;Hara et al, 2001). Thus, it was proposed that a mutant ataxin-3 mjd1a toxic cleavage fragment is released in affected but not spared neurons (Ikeda et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

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A Mutant Ataxin-3 Putative-Cleavage Fragment in Brains of Machado-Joseph Disease Patients and Transgenic Mice Is Cytotoxic above a Critical Concentration

Goti¹,

Katzen²,

Mez³

et al. 2004

J. Neurosci.

181

244

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Machado-Joseph disease (MJD) is an inherited neurodegenerative disorder caused by ataxin-3 with a polyglutamine expansion. It isproposed that a toxic cleavage fragment of mutant ataxin-3 alternatively spliced isoform mjd1a triggers neurodegeneration, although this fragment has not yet been detected in the brains of MJD patients or in animal models. We have now generated transgenic mice expressing human mutant (Q71) or normal (Q20) ataxin-3 mjd1a under the control of the mouse prion promoter. Q71 transgenic mice expressing mutant ataxin-3 mjd1a above a critical level developed a phenotype similar to MJD including progressive postural instability, gait and limb ataxia, weight loss, premature death, neuronal intranuclear inclusions, and decreased tyrosine hydroxylase-positive neurons in the substantia nigra (determined by unbiased stereology). Q20 transgenic mice had normal behavior and pathology. Brains from sick Q71 transgenic mice contained an abundant mutant ataxin-3 mjd1a putative-cleavage fragment (Fragment), which was scarce in normal Q71 transgenic mice. Reactivity of the Fragment with a panel of antibodies and comigration with truncations of mutant ataxin-3 revealed that it contained residues C terminal to amino acid 221 to include the polyglutamine expansion. A similar portion of mutant ataxin-3 mjd1a expressed in transfected neuroblastoma cells was toxic above a critical concentration. The Fragment was more abundant in two affected brain regions of MJD patients. Thus, we have developed a murine model for mutant ataxin-3 mjd1a toxicity and identified a putativecleavage fragment of the disease protein in the brains of these transgenic mice and MJD patients that is cytotoxic above a critical concentration.

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Section: Composition Of the Mutant Ataxin-3 Putative-cleavage Fragmentmentioning

confidence: 85%

Section: Introductionmentioning

confidence: 99%

A Mutant Ataxin-3 Putative-Cleavage Fragment in Brains of Machado-Joseph Disease Patients and Transgenic Mice Is Cytotoxic above a Critical Concentration

Goti¹,

Katzen²,

Mez³

et al. 2004

J. Neurosci.

181

244

View full text Add to dashboard Cite

show abstract

“…Because the expanded form of ataxin-3 is more toxic for nondividing or postmitotic cells, it may be significant that neurons are postmitotic (51). It is possible that nonneuronal cells have developed mechanisms to cope with the failure of mutant ataxin-3 to maintain efficient degradation of proteolytic substrates.…”

Section: Discussionmentioning

confidence: 99%

Ataxin-3 Interactions with Rad23 and Valosin-Containing Protein and Its Associations with Ubiquitin Chains and the Proteasome Are Consistent with a Role in Ubiquitin-Mediated Proteolysis

Doss-Pepe¹,

Stenroos²,

Johnson³

et al. 2003

Molecular and Cellular Biology

218

167

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Machado-Joseph disease is caused by an expansion of a trinucleotide CAG repeat in the gene encoding the protein ataxin-3. We investigated if ataxin-3 was a proteasome-associated factor that recognized ubiquitinated substrates based on the rationale that (i) it is present with proteasome subunits and ubiquitin in cellular inclusions, (ii) it interacts with human Rad23, a protein that may translocate proteolytic substrates to the proteasome, and (iii) it shares regions of sequence similarity with the proteasome subunit S5a, which can recognize multiubiquitinated proteins. We report that ataxin-3 interacts with ubiquitinated proteins, can bind the proteasome, and, when the gene harbors an expanded repeat length, can interfere with the degradation of a well-characterized test substrate. Additionally, ataxin-3 associates with the ubiquitin-and proteasomebinding factors Rad23 and valosin-containing protein (VCP/p97), findings that support the hypothesis that ataxin-3 is a proteasome-associated factor that mediates the degradation of ubiquitinated proteins.

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“…To ablate these neurons, we used a toxin-mediated genetic cell ablation strategy using a truncated Machado-Joseph disease gene product (ataxin-3) under the control of an MCH promoter. The ataxin-3 transgene has been used to induce apoptosis in cells in vitro and for the ablation of orexin neurons in vivo (Yoshizawa et al, 2000;Hara et al, 2001). As described below, the ablation of MCH neurons results in significant weight loss developing later in life.…”

Section: Introductionmentioning

confidence: 99%

Late-Onset Leanness in Mice with Targeted Ablation of Melanin Concentrating Hormone Neurons

Alon¹,

Friedman²

2006

J. Neurosci.

107

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The observation that loss of orexin (hypocretin) neurons causes human narcolepsy raises the possibility that other acquired disorders might also result from loss of hypothalamic neurons. To test this possibility for body weight, mice with selective loss of melanin concentrating hormone (MCH) neurons were generated. MCH was chosen to test because induced mutations of the MCH gene in mice cause hypophagia and leanness. Mice with ablation of MCH neurons were generated using toxin (ataxin-3)-mediated ablation strategy. The mice appeared normal but, after 7 weeks, developed reduced body weight, body length, fat mass, lean mass, and leptin levels. Leanness was characterized by hypophagia and increased energy expenditure. To study the role of MCH neurons on obesity secondary to leptin deficiency, we generated mice deficient in both ob gene product (leptin) and MCH neurons. Absence of MCH neurons in ob/ob mice improved obesity, diabetes, and hepatic steatosis, suggesting that MCH neurons are important mediators of the response to leptin deficiency. These data show that loss of MCH neurons can lead to an acquired leanness. This has implications for the pathogenesis of acquired changes of body weight and might be considered in clinical settings characterized by substantial weight changes later in life.

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Cell cycle arrest enhances the in vitro cellular toxicity of the truncated Machado-Joseph disease gene product with an expanded polyglutamine stretch

Cited by 63 publications

References 39 publications

A Mutant Ataxin-3 Putative-Cleavage Fragment in Brains of Machado-Joseph Disease Patients and Transgenic Mice Is Cytotoxic above a Critical Concentration

A Mutant Ataxin-3 Putative-Cleavage Fragment in Brains of Machado-Joseph Disease Patients and Transgenic Mice Is Cytotoxic above a Critical Concentration

Ataxin-3 Interactions with Rad23 and Valosin-Containing Protein and Its Associations with Ubiquitin Chains and the Proteasome Are Consistent with a Role in Ubiquitin-Mediated Proteolysis

Late-Onset Leanness in Mice with Targeted Ablation of Melanin Concentrating Hormone Neurons

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