Activation of FoxO by LRRK2 induces expression of proapoptotic proteins and alters survival of postmitotic dopaminergic neuron in Drosophila
Activation of FoxO by LRRK2 induces expression of proapoptotic proteins and alters survival of postmitotic dopaminergic neuron in Drosophila
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DOI：
10.1093/hmg/ddq289
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发表时间：
2010-10-01
影响因子：
3.5
通讯作者：
Imai, Yuzuru
中科院分区：
文献类型：
--
作者：
Kanao, Tomoko;Venderova, Katerina;Imai, Yuzuru
富含亮氨酸重复激酶 2 (LRRK2)/Dardarin 基因的错义突变（其产物编码具有多个结构域的激酶）已知会导致常染色体显性迟发性帕金森病 (PD)。在目前的研究中，我们报道了基因产物LRRK2直接磷酸化叉头盒转录因子FoxO1并增强其转录活性。研究发现该通路在果蝇中是保守的，因为果蝇 LRRK2 同源物 (dLRRK) 增强了 FoxO 的神经元毒性。重要的是，对 LRRK2/dLRRK 诱导的磷酸化具有抵抗力的 FoxO 突变体抑制了这种神经毒性。此外，我们还确定 FoxO 分别靶向果蝇和人类中的 hid 和 bim，负责 LRRK2/dLRRK 介导的细胞死亡。这些数据表明，FoxO 调节的细胞死亡分子是 LRRK2 相关 PD 神经变性过程中的关键因素。
Missense mutations in leucine-rich repeat kinase 2 (LRRK2)/Dardarin gene, the product of which encodes a kinase with multiple domains, are known to cause autosomal dominant late onset Parkinson's disease (PD). In the current study, we report that the gene product LRRK2 directly phosphorylates the forkhead box transcription factor FoxO1 and enhances its transcriptional activity. This pathway was found to be conserved in Drosophila, as the Drosophila LRRK2 homolog (dLRRK) enhanced the neuronal toxicity of FoxO. Importantly, FoxO mutants that were resistant to LRRK2/dLRRK-induced phosphorylation suppressed this neurotoxicity. Moreover, we have determined that FoxO targets hid and bim in Drosophila and human, respectively, are responsible for the LRRK2/dLRRK-mediated cell death. These data suggest that the cell death molecules regulated by FoxO are key factors during the neurodegeneration in LRRK2-linked PD.