Genetic Suppression of Polyglutamine Toxicity in
            <i>Drosophila</i>

Kazemi-Esfarjani, Parsa; Benzer, Seymour

doi:10.1126/science.287.5459.1837

Cited by 548 publications

(349 citation statements)

References 31 publications

(16 reference statements)

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“…Hsp70 and DnaJ proteins have been shown to suppress polyQ aggregation both in cells and in Drosophila. The expression of Hsp70 and DnaJB1 reduced the assembly of detergent insoluble polyQ fibrils, whilst increasing the formation of detergent soluble aggregates [29,30]. However, these results did not translate to a R6/2 mouse model of HD; Hsp70 overexpression had no significant effect on disease progression [31].…”

Section: Hd and Polyq Diseasesmentioning

confidence: 69%

Molecular chaperones and neuronal proteostasis

Smith¹,

Li²,

Cheetham³

2015

Seminars in Cell & Developmental Biology

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Protein homeostasis (proteostasis) is essential for maintaining the functionality of the proteome. The disruption of proteostasis, due to genetic mutations or an age-related decline, leads to aberrantly folded proteins that typically lose their function. The accumulation of misfolded and aggregated protein is also cytotoxic and has been implicated in the pathogenesis of neurodegenerative diseases. Neurons have developed an intrinsic protein quality control network, of which molecular chaperones are an essential component. Molecular chaperones function to promote efficient folding and target misfolded proteins for refolding or degradation. Increasing molecular chaperone expression can suppress protein aggregation and toxicity in numerous models of neurodegenerative disease; therefore, molecular chaperones are considered exciting therapeutic targets. Furthermore, mutations in several chaperones cause inherited neurodegenerative diseases. In this review, we focus on the importance of molecular chaperones in neurodegenerative diseases, and discuss the advances in understanding their protective mechanisms.

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Section: Hd and Polyq Diseasesmentioning

confidence: 69%

Molecular chaperones and neuronal proteostasis

Smith¹,

Li²,

Cheetham³

2015

Seminars in Cell & Developmental Biology

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“…Regions encoding the predicted J-and C-domains of the protein are indicated by black boxes, with residue numbers shown below; the proposed mitochondrial signal sequence is indicated by a stippled box functional and/or physical interactions in Fe-S cluster formation, makes HscB a promising candidate gene for evaluation in hereditary ataxia syndromes. This is particularly intriguing from the perspective of ataxia pathogenesis, since in a screen for second-site suppressors of polyglutamine toxicity, an important but still incompletely explained pathogenic mechanism underlying several dominant ataxia syndromes (Ross 2002;Cummings and Zoghbi 2000), the two different suppressor genes recognized encoded J proteins (Kazemi-Esfarjani and Benzer 2000). This suggests that defects in J-protein mechanisms might predispose to pathogenic processes leading to an intermediate shared with polyglutamine toxicity, both thereby producing susceptibility to ataxia (Opal and Zoghbi 2002).…”

Section: Discussionmentioning

confidence: 99%

Identification of a novel candidate gene in the iron-sulfur pathway implicated in ataxia-susceptibility: human gene encoding HscB, a J-type co-chaperone

Sun

Gargus

et al. 2003

J Hum Genet

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Iron-sulfur proteins participate in a wide range of biochemical processes, including many that are central to mitochondrial electron transfer and energy metabolism. Mutations in two such proteins, frataxin and ABCB7, cause Friedreich ataxia and X-linked sideroblastic anemia with ataxia, respectively, rendering other participants in this pathway functional candidates for hereditary ataxia syndromes. Recently frataxin was shown to have an identical phylogenetic distribution with two genes and was most likely specifically involved in the same sub-process in iron-sulfur cluster assembly as one gene, designated hscB, in bacteria. To set the stage for an analysis of the potential role of this candidate gene in human disease, we defined the human HscB cDNA, its genomic locus, and its pattern of expression in normal human tissues. The isolated human HscB cDNA spans 785 bp and encodes a conserved 235-amino-acid protein, including a putative mitochondrial import leader. The HscB gene is found at chromosome 22q11-12 and is composed of six exons and five introns. Northern blot analyses of RNA from adult and fetal tissues defined a pattern of expression in mitochondria-rich tissues similar to that of frataxin, an expression pattern compatible with its implied role in mitochondrial energetics and related disease phenotypes.

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“…Ces modèles consistent à exprimer un fragment amino-terminal du gène huntingtine humain contenant une répétition élevée du codon CAG, sous le contrôle d'un promoteur neuronal ou spécifique de la rétine [9,11]. D'autres auteurs ont simplement exprimé chez la drosophile une longue sb séquence répétée de CAG [12,13]. Dans ce dernier cas, le modèle peut être considéré plus généralement comme un modèle des maladies à expansion de polyQ.…”

Section: Les Modèles Chez La Drosophileunclassified

La chorée de Huntington chez la drosophile et chez la souris : vers de nouvelles pistes thérapeutiques ?

Liévens

Birman

2003

Med Sci (Paris)

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Genetic Suppression of Polyglutamine Toxicity in Drosophila

Cited by 548 publications

References 31 publications

Molecular chaperones and neuronal proteostasis

Molecular chaperones and neuronal proteostasis

Identification of a novel candidate gene in the iron-sulfur pathway implicated in ataxia-susceptibility: human gene encoding HscB, a J-type co-chaperone

La chorée de Huntington chez la drosophile et chez la souris : vers de nouvelles pistes thérapeutiques ?

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