Hsp104 suppresses polyglutamine-induced degeneration post onset in a drosophila MJD/SCA3 model.
Hsp104 suppresses polyglutamine-induced degeneration post onset in a drosophila MJD/SCA3 model.
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DOI：
10.1371/journal.pgen.1003781
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发表时间：
2013
期刊：
影响因子：
4.5
通讯作者：
Shorter J
中科院分区：
文献类型：
--
作者：
Cushman-Nick M;Bonini NM;Shorter J
目前还没有有效的疗法来拮抗或逆转支撑聚谷氨酰胺(PolyQ)疾病的蛋白质错误折叠事件，包括脊髓小脑性共济失调3型(SCA3)。在这里，我们用Hsp104来增强果蝇SCA3模型的蛋白质平衡网络，Hsp104是一种来自酵母的强大的蛋白质解聚酶，令人费解地在后生动物中缺失。Hsp104抑制了由含有致病多聚Q链的C末端ataxin-3(MJD)片段引起的眼部变性，但意外地增强了全长致病MJD的聚集性和毒性。Hsp104抑制缺少部分N末端去泛素酶结构域的MJD变体和不能与多泛素结合的全长MJD变体的毒性，表明MJD-泛素相互作用阻碍了保护性HSP104模式。重要的是，在分期实验中，Hsp104在多聚Q诱导的变性开始后表达时抑制了C-末端MJD片段的毒性，而Hsp70无效。因此，我们建立了第一个在致病蛋白诱导的变性开始后给予的解聚酶或伴侣治疗，以减缓疾病的进展。目前还没有有效的疗法来治疗由扩张的聚谷氨酰胺(PolyQ)束引起的任何神经退行性疾病，包括脊髓小脑性共济失调3型(SCA3)。这些疾病与受影响个体神经元中带有扩展的多聚Q链的蛋白质的错误折叠和聚集有关。在SCA3中，ataxin-3(MJD)是一种承受多Q扩张并形成不可溶聚集体的蛋白质。在这里，作为一种治疗策略，我们将Hsp104，一种来自酵母的强大的蛋白质解聚酶引入到果蝇的SCA3模型中。HSP104在动物中没有同源物，但在体外具有溶解多聚Q聚集体的不同寻常的能力，这一活性可以用于治疗。事实上，Hsp104抑制了由C-末端ataxin-3(MJD)片段引起的退化，该片段包含在疾病中积累的致病扩展多聚体。然而，Hsp104增强了全长致病性MJD的聚集性和毒性。HSP104挽救了不能与多泛素结合或在去泛素酶结构域缺失的MJD形式，表明MJD-泛素相互作用阻碍了保护性HSP104的活性。重要的是，Hsp104在多聚Q诱导的变性开始后表达时抑制了C末端MJD片段的毒性，而Hsp70无效。因此，我们建立了第一个在致病蛋白诱导的变性开始后给予的解聚酶或伴侣治疗，以减缓疾病的进展。
There are no effective therapeutics that antagonize or reverse the protein-misfolding events underpinning polyglutamine (PolyQ) disorders, including Spinocerebellar Ataxia Type-3 (SCA3). Here, we augment the proteostasis network of Drosophila SCA3 models with Hsp104, a powerful protein disaggregase from yeast, which is bafflingly absent from metazoa. Hsp104 suppressed eye degeneration caused by a C-terminal ataxin-3 (MJD) fragment containing the pathogenic expanded PolyQ tract, but unexpectedly enhanced aggregation and toxicity of full-length pathogenic MJD. Hsp104 suppressed toxicity of MJD variants lacking a portion of the N-terminal deubiquitylase domain and full-length MJD variants unable to engage polyubiquitin, indicating that MJD-ubiquitin interactions hinder protective Hsp104 modalities. Importantly, in staging experiments, Hsp104 suppressed toxicity of a C-terminal MJD fragment when expressed after the onset of PolyQ-induced degeneration, whereas Hsp70 was ineffective. Thus, we establish the first disaggregase or chaperone treatment administered after the onset of pathogenic protein-induced degeneration that mitigates disease progression. There are no effective therapeutics for any of the neurodegenerative disorders caused by expanded polyglutamine (PolyQ) tracts including Spinocerebellar Ataxia Type-3 (SCA3). These disorders are connected with the misfolding and aggregation of proteins bearing expanded PolyQ tracts in the neurons of affected individuals. In SCA3, ataxin-3 (MJD) is the protein that bears the PolyQ expansion and forms insoluble aggregates. Here, as a therapeutic strategy we introduce Hsp104, a powerful protein disaggregase from yeast, into Drosophila models of SCA3. Hsp104 has no homologue in animals, but has an unusual ability to dissolve PolyQ aggregates in vitro, an activity that could be harnessed therapeutically. Indeed, Hsp104 suppressed degeneration caused by a C-terminal ataxin-3 (MJD) fragment containing the pathogenic expanded PolyQ tract, which accumulates in disease. However, Hsp104 enhanced aggregation and toxicity of full-length pathogenic MJD. Hsp104 rescued forms of MJD unable to engage polyubiquitin or with a deletion in the deubiquitylase domain indicating that MJD-ubiquitin interactions hinder protective Hsp104 activities. Importantly, Hsp104 suppressed toxicity of a C-terminal MJD fragment when expressed after the onset of PolyQ-induced degeneration, whereas Hsp70 was ineffective. Thus, we establish the first disaggregase or chaperone treatment administered after the onset of pathogenic protein-induced degeneration that mitigates disease progression.
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影响因子：
64.5
作者：
DeSantis ME;Leung EH;Sweeny EA;Jackrel ME;Cushman-Nick M;Neuhaus-Follini A;Vashist S;Sochor MA;Knight MN;Shorter J
通讯作者：
Shorter J
影响因子：
2.5
作者：
Dandoy-Dron, Francoise;Bogdanova, Anna;Dron, Michel
通讯作者：
Dron, Michel
DOI：
10.1073/pnas.0706006104
发表时间：
2007-12-04
影响因子：
11.1
作者：
Feigin, Andrew;Kaplitt, Michael G.;Eidelberg, David
通讯作者：
Eidelberg, David
影响因子：
16.8
作者：
DiSalvo, Susanne;Derdowski, Aaron;Serio, Tricia R.
通讯作者：
Serio, Tricia R.
Machado-Joseph疾病：从最初描述到新的观点。
影响因子：
3.7
作者：
Bettencourt C;Lima M
通讯作者：
Lima M