Analysis of the molecular mechanism by which the genes for early‐onset parkinson's disease regulate mitochondrial maintenance

早发性帕金森病基因调控线粒体维持的分子机制分析

• 批准号: 23790973
• 负责人: IMAI Yuzuru
• 金额: $ 2.75万
• 依托单位: Juntendo University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Young Scientists (B)
• 财政年份: 2011
• 资助国家: 日本
• 起止时间: 2011 至 2012
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-23790973/
• 关键词: パーキンソン病; PINK1; Parkin; 神経変性疾患; ドーパミン神経; ショウジョウバエ; ミトコンドリア; キナーゼ; ユビキチンリガーゼ; リン酸化; 脳神経疾患; Miro; 神経軸索輸送

Mitochondrial dysregulation is now implicated in various human diseases including cancer, diabetes, myopathy and neurodegeneration. The pathological hallmark of the second most common neurodegenerative disorder PDis the progressive degeneration of dopaminergic neurons in the midbrain.A series of elegant studies have demonstrated that two Parkinson’s disease(PD)-associated genes PINK1and parkinare involved in the maintenance of healthy mitochondria. Parkin in co-operation with PINK1 specifically recognises damaged mitochondria with reduced mitochondrial membrane potential (Δψm), rapidly isolates them from the mitochondrial network and eliminates them through the ubiquitin-proteasome and autophagy pathways. Our studies combined with Drosophilagenetics and cell biologycontributedto understanding the molecular mechanisms of PINK1 and Parkin-mediated mitochondrial regulation and the pathological mechanisms how defects in the PINK1-Parkin pathway leads toneurodegeneration in PD.

线粒体失调现在与多种人类疾病有关，包括癌症、糖尿病、肌病和神经变性。第二种最常见的神经退行性疾病的病理特征是中脑多巴胺能神经元的进行性变性。一系列精美的研究表明，两种帕金森病。 (PD) 相关基因 PINK1 和 Parkina 参与维护健康的线粒体 Parkin 与 PINK1 合作特异性识别受损的线粒体。我们的研究结合果蝇遗传学和细胞生物学，有助于了解 PINK1 和 Parkin 介导的线粒体调节的分子机制和病理机制。 PINK1-Parkin 通路缺陷如何导致 PD 神经变性。

项目成果

Animal models of Parkinson's disease

帕金森病动物模型

• 发表时间: 2012
• 作者: Imai Y; Venderova K; Lim K
• 通讯作者: Lim K

PINK1-mediated phosphorylation of the Parkin ubiquitin-like domain primes mitochondrial translocation of Parkin and regulates mitophagy

PINK1 介导的 Parkin 泛素样结构域磷酸化引发 Parkin 线粒体易位并调节线粒体自噬

• DOI: 10.1038/srep01002
• 发表时间: 2012
• 影响因子: 4.6
• 作者: Kahori Shiba

パーキンソン病発症に関わる新規分子メカニズムの発見 ~新規治療ターゲットとしての可能性 ~

发现与帕金森病发病相关的新分子机制~作为新治疗靶点的可能性~

Tricornered/NDR kinase signaling mediates PINK1-directed mitochondrial quality control and tissue maintenance

Tricornered/NDR 激酶信号传导介导 PINK1 定向线粒体质量控制和组织维护

• DOI: 10.1101/gad.203406.112
• 发表时间: 2013
• 作者: Wu Z; Sawada T; Shiba K; Liu S; Kanao T; Takahashi R; Hattori N; Imai Y; Lu B. .
• 通讯作者: Lu B. .

PINK1-mediated phosphorylation of the Parkin ubiquitin-like domain primes mitochondrial translocation of Parkin and regulates mitophagy

PINK1 介导的 Parkin 泛素样结构域磷酸化引发 Parkin 线粒体易位并调节线粒体自噬

• 发表时间: 2012
• 作者: Shiba