Wild-Type Huntingtin Protects from Apoptosis Upstream of Caspase-3

Rigamonti, Dorotea; Bauer, Johannes H.; De-Fraja, Claudio; Conti, Luciano; Sipione, Simonetta; Sciorati, Clara; Clementi, Emilio; Hackam, Abigail S.; Hayden, Michael R.; Li, Yong; Cooper, Joseph; Ross, Christopher A.; Govoni, Stefano; Vincenz, Claudius; Cattaneo, Elena

doi:10.1523/jneurosci.20-10-03705.2000

Cited by 351 publications

(247 citation statements)

References 42 publications

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“…We also identified several genes implicated in apoptosis, such as the Huntington disease gene Huntingtin, the double-strand DNA break repair gene hRAD54 (expressed higher in anaplastic tumors than in FH tumors), gamma-interferon-inducible gene IFI16 and caspase-10 (expressed lower in anaplastic tumors than in FH tumors). Wild-type Huntingtin has been shown to be antiapoptotic by inhibiting the conversion of procaspase-9 into active caspase-9 (Rigamonti et al, 2000). Huntingtin also regulates the transcription of BDNF (Zuccato et al, 2001).…”

Section: An Expression Signature For Anaplastic Wilms Tumormentioning

confidence: 99%

Transcript profiling of Wilms tumors reveals connections to kidney morphogenesis and expression patterns associated with anaplasia

Kessler

Williams

2004

Oncogene

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Anaplasia (unfavorable histology) is associated with therapy resistance and poor prognosis of Wilms tumor, but the molecular basis for this phenotype is unclear. Here, we used a cDNA array with 9240 clones relevant to cancer biology and/or kidney development to examine the expression profiles of 54 Wilms tumors, five normal kidneys and fetal kidney. By linking genes differentially expressed between fetal kidney and Wilms tumors to kidney morphogenesis, we found that genes expressed at a higher level in Wilms tumors tend to be expressed more in uninduced metanephrogenic mesenchyme or blastema than in their differentiated structures. Conversely, genes expressed at a lower level in Wilms tumors tend to be expressed less in uninduced metanephrogenic mesenchyme or blastema. We also identified 97 clones representing 76 Unigenes or unclustered ESTs that clearly separate anaplastic Wilms tumors from tumors with favorable histology. Genes in this set provide insight into the nature of the abnormal nuclear morphology of anaplastic tumors and may facilitate identification of molecular targets to improve their responsiveness to treatment.

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Section: An Expression Signature For Anaplastic Wilms Tumormentioning

confidence: 99%

Transcript profiling of Wilms tumors reveals connections to kidney morphogenesis and expression patterns associated with anaplasia

Kessler

Williams

2004

Oncogene

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“…39(1), [38][39][40][41][42][43][44][45][46] 2007 toxic to neurons and is related to cellular toxicity (Davies et al, 1997;DiFiglia et al, 1997; Cooper et al., 1998;Zala et al, 2005;Benchoua et al, 2006). The activations of caspase-3 or calpain cleaves huntingtin to produce 60-80 kDa sized N-terminal fragments (Jaattela et al, 1998;Wellington et al, 1998;Rigamonti et al, 2000;Kim et al, 2003). Experiments performed in cloned striatal cells have shown that z-VAD-FMK, a broad-spectrum caspase inhibitor, blocks the cleavage of the N-terminal product and increases cell survival (Kim et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

Heat shock protein 70 alters the endosome-lysosomal localization of huntingtin

Kang

Ahn²,

Kim³

et al. 2007

Exp Mol Med

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Huntington's disease is caused by CAG trinucleotide expansions in the gene encoding huntingtin. Nterminal fragments of huntingtin with polyglutamine produce aggregates in the endosome-lysosomal system, where proteolytic fragments of huntingtin is generated. Heat shock protein 70 (HSP70) prevents the formation of protein aggregates, but the effect of HSP70 on the huntingtin in the endosome-lysosomal system is unknown. This study was to determine whether HSP70 alters the distribution of huntingtin in endosome-lysosomal system. HSP70 expressing stable cells (NIH/3T3 or cerebral hybrid cell line A1) were generated, and mutant [(CAG) 100 ] huntingtin was transiently overexpressed. Analysis of subcellular distribution by immnuocytochemistry or proteolysis cleavage by Western blotting was performed. 18 CAG repeat wild type [WT; (CAG)18] huntingtin was used as a control. Cells with huntingtin showed patterns of endosomelysosomal accumulation, from a 'dispersed vacuole (DV)' type into a coalescent 'perinuclear vacuole (PV)' type over time. In WT huntingtin, HSP70 increased the cells with the PV types that enhanced the proteolytic cleavage of huntingtin. However, HSP70 reduced cells of the DV and PV types expressing mutant huntingtin, that result in less proteolysis than that of control. In addition, intranuclear inclusions were formed only in mutant cells, which was not affected by HSP70. These results suggest that HSP70 alters the distribution of huntingtin in the endosomelysosomal system, and that this contributes to huntingtin proteolysis.Keywords: endosomes; HSP70 heat-shock proteins; Huntington disease; lysosome IntroductionHuntington's disease (HD) is an autosomal dominant neurodegenerative disorder characterized by progressive chorea leading to severe debilitation and death within 15-20 years. Selective neuronal loss in the neostriatum and cortex causes choreic movement and dementia (Ross et al., 1997). The gene defective in HD is located on chromosome 4p16.3 (Lesperance et al., 1995) and is translated into huntingtin, a 350 kDa ubiquitous protein (Ide et al., 1995;Sharp et al., 1995). Moreover, increased CAG trinucleotide repeats in exon 1 lead to polyglutamine expansion in the N-terminus of huntingtin and are responsible for neurodegeneration in the HD brain (MacDonald et al., 1993, The Huntington's Disease Collaborative Research Group). The intracellular aggregates observed in the HD human brain and in transgenic mice are mainly formed by proteolysis of the N-terminus region in mutant huntingtin (Davies et al., 1997;DiFiglia et al., 1997), and are related to cellular toxicity (Cooper et al., 1998;Zala et al., 2005;Benchoua et al., 2006;Scheibel and Buchner, 2006).In dying neurons of the HD brain, huntingtinHeat shock protein 70 alters the endosome-lysosomal localization of huntingtin Huntingtin and HSP70 39 aberrantly accumulates in perinuclear regions and in numerous punctate cytoplasmic structures that resemble the endosomal-lysosomal system (Sapp et al., 1997). In an in vitro model of HD, using a ...

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“…Indeed, normal huntingtin is antiapoptotic in brain cells (1,2,5,31) and is also found to protect from toxicity induced by the mutant protein (3,4) and to support the production of cortically derived BDNF (10).…”

Section: Proteolysis Of Huntingtin In Primary Neuronsmentioning

confidence: 99%

“…Huntingtin is a 348-kDa cytoplasmic protein that is important for cell survival (1)(2)(3)(4)(5). Interest in this protein stems from the fact that mutation into the encoding gene causes HD, a slowly progressing neurodegenerative disease characterized by the selective death of the striatal and cortical neurons (6).…”

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Calcium-dependent Cleavage of Endogenous Wild-type Huntingtin in Primary Cortical Neurons

Goffredo

Rigamonti

Tartari

et al. 2002

Journal of Biological Chemistry

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Huntington's disease (HD) is caused by a polyglutamine expansion in the amino-terminal region of huntingtin. Mutant huntingtin is proteolytically cleaved by caspases, generating amino-terminal aggregates that are toxic for cells. The addition of calpains to total brain homogenates also leads to cleavage of wild-type huntingtin, indicating that proteolysis of mutant and wildtype huntingtin may play a role in HD. Here we report that endogenous wild-type huntingtin is promptly cleaved by calpains in primary neurons. Exposure of primary neurons to glutamate or 3-nitropropionic acid increases intracellular calcium concentration, leading to loss of intact full-length wild-type huntingtin. This cleavage could be prevented by calcium chelators and calpain inhibitors. Degradation of wild-type huntingtin by calcium-dependent proteases thus occurs in HD neurons, leading to loss of wild-type huntingtin neuroprotective activity.Huntingtin is a 348-kDa cytoplasmic protein that is important for cell survival (1-5). Interest in this protein stems from the fact that mutation into the encoding gene causes HD, a slowly progressing neurodegenerative disease characterized by the selective death of the striatal and cortical neurons (6).In the pathology, the amino-terminal portion of huntingtin is characterized by an expanded polyglutamine stretch conferring a newly acquired toxic function to the protein (7). Several observations implicate mutant huntingtin proteolysis in the pathogenesis of HD 1 because amino-terminal huntingtin fragments aggregate into the nucleus and cytoplasm of human neurons and overexpression of these fragments in vitro causes cell death (8).Despite the genetic and experimental evidence indicating a gain of function mechanism in HD, loss of normal huntingtin function may also be important (9). Normal huntingtin is antiapoptotic (1, 5) and exerts a peculiar function for striatal neurons, given that it sustains the production of cortically derived BDNF, which they depend on for their activity (10). Proteolysis of wild-type huntingtin may cause loss of these physiological function(s). However, thus far, most of the research on the role of proteolysis in HD has been directed toward analysis of mutant huntingtin. Mutant huntingtin is cleaved by caspases at residues 513 and 552. Mutation at these sites impairs caspase-3 cleavage and shows reduced toxicity after transfection in neuronal cells (11). Furthermore, transfection of cortical neurons with mutant huntingtin in the presence of the broad spectrum caspase inhibitor z-VAD-fmk blocks cleavage of exogenous huntingtin and reduces cell toxicity (12). Moreover, in HD-transgenic mice, caspase inhibition results in delayed onset of symptoms, slowed progression, and prolonged survival (13,14).Other proteases different from caspases may also be involved. Indeed, analyses of huntingtin proteolysis in HD postmortem brains have revealed fragments in the cortex and striatum not justified by caspase cleavage alone (15, 16). More recently, the possibility that wild-type huntingt...

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Wild-Type Huntingtin Protects from Apoptosis Upstream of Caspase-3

Cited by 351 publications

References 42 publications

Transcript profiling of Wilms tumors reveals connections to kidney morphogenesis and expression patterns associated with anaplasia

Transcript profiling of Wilms tumors reveals connections to kidney morphogenesis and expression patterns associated with anaplasia

Heat shock protein 70 alters the endosome-lysosomal localization of huntingtin

Calcium-dependent Cleavage of Endogenous Wild-type Huntingtin in Primary Cortical Neurons

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