dAtaxin-2 mediates expanded Ataxin-1-induced neurodegeneration in a Drosophila model of SCA1.
dAtaxin-2 mediates expanded Ataxin-1-induced neurodegeneration in a Drosophila model of SCA1.
复制标题
DOI：
10.1371/journal.pgen.0030234
复制
发表时间：
2007-12-28
期刊：
影响因子：
4.5
通讯作者：
Botas J
中科院分区：
文献类型：
--
作者：
Al-Ramahi I;Pérez AM;Lim J;Zhang M;Sorensen R;de Haro M;Branco J;Pulst SM;Zoghbi HY;Botas J
脊髓小脑共济失调（SCA）是一组遗传异质性神经退行性疾病，共同特征是小脑萎缩。SCA 1和SCA 2分别是由共济失调蛋白-1（ATXN 1）和共济失调蛋白-2（ATXN 2）中的多聚谷氨酰胺束扩张引起的两种共济失调，这两种蛋白质在其他方面是不相关的。在这里，我们使用SCA 1果蝇模型揭示SCA 1发病过程中Ataxin-1与Ataxin-2的分子机制。我们表明，野生型果蝇Ataxin-2（dAtx 2）是人类扩展Ataxin-1（Ataxin-1[82 Q]）毒性的主要遗传修饰剂。增加的dAtx 2水平增强，更重要的是，降低的dAtx 2水平抑制Ataxin-1[82 Q]诱导的神经变性，从而排除了dAtx 2耗竭的致病机制。虽然Ataxin-2通常是细胞质和Ataxin-1核，我们表明，dAtx 2和hAtaxin-2物理相互作用与Ataxin-1。此外，我们表明，扩大Ataxin-1诱导dAtx 2/hAtaxin-2在果蝇和SCA 1死后神经元的核内积累。这些观察结果表明，Ataxin-2的核积累有助于扩展Ataxin-1诱导的毒性。我们用核定位信号（NLS）和核输出信号（内斯）工程化dAtx 2转基因来检验这一假设。我们发现NLS-dAtx 2而不是NES-dAtx 2模拟了由共济失调蛋白-1 [82 Q]引起的神经退行性表型，包括对前神经因子Seneless的抑制。总之，这些发现揭示了具有共同临床特征但病因不同的神经退行性疾病之间的先前未知的功能联系。脊髓小脑共济失调（SCA）是一组由多种无关基因的不同类型突变引起的神经退行性疾病。例如，SCA 1和SCA 2是由Ataxin-1和Ataxin-2的突变引起的，这两种蛋白质仅在名称上相关。尽管存在这些差异，但大多数SCA在临床和神经病理学上有许多惊人的相似之处，如共济失调、震颤、言语困难以及小脑和脑干萎缩。此外，许多引起共济失调的蛋白质共享相互作用的蛋白质伴侣。总之，这些观察结果表明，许多SCA也有共同的发病机制。在这里，我们报告以前未知的功能之间的相互作用的基因和蛋白质负责SCA 1和SCA 2。我们发现，Ataxin-1和Ataxin-2物理相互作用，突变体Ataxin-1迫使Ataxin-2在细胞核而不是细胞质中积累。最重要的是，使用动物模型，我们发现果蝇Ataxin-2基因是Ataxin-1诱导的神经毒性的强抑制剂。因此，神经元变性可能通过不同SCA中的共同机制发生。这些发现为这些目前尚无有效治疗方法的神经退行性疾病提供了未来的共同疗法。
Spinocerebellar ataxias (SCAs) are a genetically heterogeneous group of neurodegenerative disorders sharing atrophy of the cerebellum as a common feature. SCA1 and SCA2 are two ataxias caused by expansion of polyglutamine tracts in Ataxin-1 (ATXN1) and Ataxin-2 (ATXN2), respectively, two proteins that are otherwise unrelated. Here, we use a Drosophila model of SCA1 to unveil molecular mechanisms linking Ataxin-1 with Ataxin-2 during SCA1 pathogenesis. We show that wild-type Drosophila Ataxin-2 (dAtx2) is a major genetic modifier of human expanded Ataxin-1 (Ataxin-1[82Q]) toxicity. Increased dAtx2 levels enhance, and more importantly, decreased dAtx2 levels suppress Ataxin-1[82Q]-induced neurodegeneration, thereby ruling out a pathogenic mechanism by depletion of dAtx2. Although Ataxin-2 is normally cytoplasmic and Ataxin-1 nuclear, we show that both dAtx2 and hAtaxin-2 physically interact with Ataxin-1. Furthermore, we show that expanded Ataxin-1 induces intranuclear accumulation of dAtx2/hAtaxin-2 in both Drosophila and SCA1 postmortem neurons. These observations suggest that nuclear accumulation of Ataxin-2 contributes to expanded Ataxin-1-induced toxicity. We tested this hypothesis engineering dAtx2 transgenes with nuclear localization signal (NLS) and nuclear export signal (NES). We find that NLS-dAtx2, but not NES-dAtx2, mimics the neurodegenerative phenotypes caused by Ataxin-1[82Q], including repression of the proneural factor Senseless. Altogether, these findings reveal a previously unknown functional link between neurodegenerative disorders with common clinical features but different etiology. The spinocerebellar ataxias (SCAs) are a group of ∼30 neurodegenerative disorders caused by different types of mutations in a variety of unrelated genes. For example, SCA1 and SCA2 are caused by mutations in Ataxin-1 and Ataxin-2, two proteins related in name only. Despite these differences, most SCAs share a number of striking clinical and neuropathological similarities, such as ataxia, tremor, speech difficulties, and atrophy of the cerebellum and brainstem. In addition, many ataxia-causing proteins share interacting protein partners. Together, these observations suggest that many SCAs also share common mechanisms of pathogenesis. Here, we report previously unknown functional interactions between the genes and proteins responsible for SCA1 and SCA2. We find that Ataxin-1 and Ataxin-2 physically interact, and that mutant Ataxin-1 forces Ataxin-2 to accumulate in the nucleus instead of the cytoplasm. Most importantly, using an animal model, we discovered that the Drosophila Ataxin-2 gene is a strong suppressor of Ataxin-1-induced neurotoxicity. Thus, neuronal degeneration may take place through common mechanisms in different SCAs. These findings open the possibility of future common therapies for these neurodegenerative disorders for which there is no effective treatment.
登录
查看更多内容
影响因子：
16.2
作者：
Gunawardena, S;Her, LS;Goldstein, LSB
通讯作者：
Goldstein, LSB
影响因子：
3.9
作者：
GANETZKY, B;FLANAGAN, JR
通讯作者：
FLANAGAN, JR
影响因子：
30.8
作者：
Huynh, DP;Figueroa, K;Pulst, SM
通讯作者：
Pulst, SM
影响因子：
4.5
作者：
Kaltenbach LS;Romero E;Becklin RR;Chettier R;Bell R;Phansalkar A;Strand A;Torcassi C;Savage J;Hurlburt A;Cha GH;Ukani L;Chepanoske CL;Zhen Y;Sahasrabudhe S;Olson J;Kurschner C;Ellerby LM;Peltier JM;Botas J;Hughes RE
通讯作者：
Hughes RE
影响因子：
3.5
作者：
Huynh, DP;Yang, HT;Pulst, SM
通讯作者：
Pulst, SM