Suppression of aggregate formation and apoptosis by transglutaminase inhibitors in cells expressing truncated DRPLA protein with an expanded polyglutamine stretch

Igarashi, Shuichi; Koide, Reiji; Shimohata, Takayoshi; Yamada, Mitsunori; Hayashi, Yasuko; Takano, Hiroki; Date, Hidetoshi; Oyake, Mutsuo; Sato, Toshiya; Sato, Aki; Egawa, Shigekimi; Ikeuchi, Takeshi; Tanaka, Hajime; Nakano, Ryoichi; Tanaka, Keiko; Hozumi, Isao; Ishii, Takashi; Takahashi, Hitoshi; Tsuji, Shoji

doi:10.1038/ng0298-111

Cited by 352 publications

(225 citation statements)

References 37 publications

Supporting

Mentioning

218

Contrasting

Order By: Relevance

“…B (1999) 354, 1047^1055 expansion diseases. One line of evidence for nuclear involvement is the exclusive nuclear localization of aggregates in post-mortem brains in SCA-1 (Skinner et al 1997), SCA-3 (Paulson et al 1997), SCA-7 (Holmberg et al 1998) and DRPLA (Igarashi et al 1998;Becher et al 1998). Intranuclear aggregates were also observed in mice transgenic for a hypoxanthine phosphoribosyl transferase (HPRT) gene containing an expanded polyglutamine stretch and in mice expressing exon 1 of the HD gene Ordway et al 1997).…”

Section: Introductionmentioning

confidence: 94%

“…Third, increasing frequency of aggregates is associated with increasing toxicity in in vitro models of HD, DRPLA and SBMA (Ellerby et al 1999;Hackam et al 1998a;Igarashi et al 1998). Further, decreasing the frequency of aggregates in vitro results in reduced toxicity (Ellerby et al 1999;Igarashi et al 1998). However, despite these data suggesting a causal relationship, none can di¡erentiate between aggregates as being crucial to pathogenesis, from being markers of pathology.…”

Section: Introductionmentioning

confidence: 96%

“…Several lines of evidence from patient samples, transgenic mice and cell culture models suggest that the aggregates are associated with the pathology of CAG expansion diseases. First, the inclusions are only observed in the brains of individuals carrying the disease allele, and are present predominantly in regions and neuronal populations a¡ected by the disease Gour¢nkel-An et al 1998;Sapp et al 1997;Paulson et al 1997;Igarashi et al 1998;Skinner et al 1997;Becher et al 1998;. Second, neuronal inclusions have also been observed in mice transgenic for genes with expanded CAG tracts, which develop inclusions prior to the onset of neurological symptoms Ordway et al 1997;Skinner et al 1997).…”

Section: Introductionmentioning

confidence: 98%

“…Second, neuronal inclusions have also been observed in mice transgenic for genes with expanded CAG tracts, which develop inclusions prior to the onset of neurological symptoms Ordway et al 1997;Skinner et al 1997). Third, increasing frequency of aggregates is associated with increasing toxicity in in vitro models of HD, DRPLA and SBMA (Ellerby et al 1999;Hackam et al 1998a;Igarashi et al 1998). Further, decreasing the frequency of aggregates in vitro results in reduced toxicity (Ellerby et al 1999;Igarashi et al 1998).…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Evidence for both nucleus and cytoplasm as subcellular sites of pathogenesis in Huntington'sdisease in cell culture and in transgenic mice expressing mutant huntingtin

Hackam

Hodgson

Singaraja

et al. 1999

Phil. Trans. R. Soc. Lond. B

View full text Add to dashboard Cite

A unifying feature of the CAG expansion diseases is the formation of intracellular aggregates composed of the mutant polyglutamine-expanded protein. Despite the presence of aggregates in a¡ected patients, the precise relationship between aggregates and disease pathogenesis is unresolved. Results from in vivo and in vitro studies of mutant huntingtin have led to the hypothesis that nuclear localization of aggregates is critical for the pathology of Huntington's disease (HD). We tested this hypothesis using a 293T cell culture model system by comparing the frequency and toxicity of cytoplasmic and nuclear huntingtin aggregates. Insertion of nuclear import or export sequences into huntingtin fragments containing 548 or 151 amino acids was used to reverse the normal localization of these proteins. Changing the subcellular localization of the fragments did not in£uence their total aggregate frequency. There were also no signi¢cant di¡erences in toxicity associated with the presence of nuclear compared with cytoplasmic aggregates. These studies, together with ¢ndings in transgenic mice, suggest two phases for the pathogenesis of HD, with the initial toxicity in the cytoplasm followed by proteolytic processing of huntingtin, nuclear translocation with increased nuclear concentration of N-terminal fragments, seeding of aggregates and resultant apoptotic death. These ¢ndings support the nucleus and cytosol as subcellular sites for pathogenesis in HD.

show abstract

Section: Introductionmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Evidence for both nucleus and cytoplasm as subcellular sites of pathogenesis in Huntington'sdisease in cell culture and in transgenic mice expressing mutant huntingtin

Hackam

Hodgson

Singaraja

et al. 1999

Phil. Trans. R. Soc. Lond. B

View full text Add to dashboard Cite

show abstract

“…Disease genes share no sequence homology except for the poly-Q coding sequences, indicating a critical role of the glutamine expansion in pathogenesis (Igarashi et al, 1998). In addition to DRPLA, expression of poly-Q expanded mutant proteins identified in HD, SCA1, SCA3, or SCA7 also induced neurodegeneration in mice (Mangiarini et al, 1996;Clark et al, 1997;Davies et al, 1997;Yvert et al, 2000;Cemal et al, 2002;Benn et al, 2005).…”

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

View full text Add to dashboard Cite

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.

show abstract

?Tissue? transglutaminase release from apoptotic cells into extracellular matrix during human liver fibrogenesis

et al. 1999

View full text Add to dashboard Cite

Enhanced apoptosis characterizes several pathologies affecting human liver. This study sought to determine whether apoptosis is involved in the formation of fibrotic lesions occurring in hepatic disease. The expression of Bcl‐2 was analysed, and of ‘tissue’ transglutaminase (tTG), a cross‐linking enzyme which recent evidence suggests plays a role in the formation of fibrotic lesions in experimental settings. Regardless of the degree of liver injury, tTG abnormally accumulated in the liver cells adjacent to fibrotic tissue. Many cells showing DNA fragmentation and morphological features of apoptosis were also observed near fibrotic lesions. Bcl‐2 was detected predominantly in infiltrating lymphocytes within the liver tissue. Marked staining for both tTG protein and chromatin was also observed in the acellular fibrotic tissue, which suggested an active release of intracellular macromolecules from the dying cells into the extracellular matrix. This study indicates that fibrogenesis in the liver is associated with the release of tTG from dying cells. By cross‐linking extracellular matrix proteins, this enzyme might play a role in the formation of fibrotic lesions. Copyright © 1999 John Wiley & Sons, Ltd.

show abstract

Suppression of aggregate formation and apoptosis by transglutaminase inhibitors in cells expressing truncated DRPLA protein with an expanded polyglutamine stretch

Cited by 352 publications

References 37 publications

Evidence for both nucleus and cytoplasm as subcellular sites of pathogenesis in Huntington'sdisease in cell culture and in transgenic mice expressing mutant huntingtin

Evidence for both nucleus and cytoplasm as subcellular sites of pathogenesis in Huntington'sdisease in cell culture and in transgenic mice expressing mutant huntingtin

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

?Tissue? transglutaminase release from apoptotic cells into extracellular matrix during human liver fibrogenesis

Contact Info

Product

Resources

About