Pathogenic polyglutamine proteins cause dendrite defects associated with specific actin cytoskeletal alterations in Drosophila
Pathogenic polyglutamine proteins cause dendrite defects associated with specific actin cytoskeletal alterations in Drosophila
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DOI：
10.1073/pnas.1113573108
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发表时间：
2011-10-04
影响因子：
11.1
通讯作者：
Jan, Yuh-Nung
中科院分区：
文献类型：
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作者：
Lee, Sung Bae;Bagley, Joshua A.;Jan, Yuh-Nung
虽然与各种多聚谷氨酰胺（polyQ）疾病相关的神经退行性病变已经促使对polyQ诱导的细胞死亡进行了广泛的研究，但通常出现在疾病晚期的神经元损失可能无法解释先前的运动和精神障碍。在神经元细胞死亡之前polyQ诱导的神经元功能障碍的细胞基础在很大程度上仍然未知。在这里，我们报告缺陷的树突形态发生在一个特定的神经元亚群，由于聚Q毒性，可以从半胱天冬酶依赖性细胞死亡解离。表达致病性脊髓小脑共济失调1型（SCA 1）或3型（SCA 3）蛋白质在果蝇幼虫树突状神经元引起神经元类型特异性树突表型主要影响终端分支。我们进一步表明，致病polyQ蛋白在成年果蝇神经元树突形成后的表达也大大降低了树突的复杂性。这些缺陷与树突状F-肌动蛋白结构的破坏有关，这可以通过增加Rac-PAK信号传导来部分减轻。总之，这些研究结果表明，特定的肌动蛋白细胞骨架的改变，改变树突的形态和功能可能有助于至少一个子集的polyQ疾病，包括SCA 3和SCA 1的发病机制。
Whereas the neurodegeneration associated with various polyglutamine (polyQ) diseases has prompted extensive studies of polyQ-induced cell death, the neuronal loss that typically appears during late stages of the diseases may not account for the preceding movement and mental disorders. The cellular basis for polyQ-induced neuronal dysfunction preceding neuronal cell death remains largely unknown. Here we report defective dendrite morphogenesis within a specific subset of neurons due to polyQ toxicity that can be dissociated from caspase-dependent cell death. Expressing pathogenic spinocerebellar ataxia type 1 (SCA1) or type 3 (SCA3) proteins in Drosophila larval dendritic arborization neurons caused neuronal type-specific dendrite phenotypes primarily affecting terminal branches. We further show that expression of pathogenic polyQ proteins in adult flies after the formation of neuronal dendrites also greatly reduced dendritic complexity. These defects are associated with disruption of dendritic F-actin structures that can be partially mitigated by increasing Rac-PAK signaling. Together, these findings suggest that specific actin cytoskeletal alterations that alter dendrite morphology and function may contribute to the pathogenesis of at least a subset of polyQ disorders, including SCA3 and SCA1.