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.

线粒体失调现在与各种人类疾病有关，包括癌症、糖尿病、肌病和神经变性。帕金森病（Parkinson's disease，PD）是第二大常见的神经退行性疾病，其病理特征是中脑多巴胺能神经元的进行性变性，一系列研究表明，帕金森病（Parkinson's disease，PD）相关基因PINK 1和parkin参与维持健康的线粒体。Parkin与PINK 1合作，特异性地识别线粒体膜电位（Δ Km）降低的受损线粒体，迅速将其从线粒体网络中分离出来，并通过泛素-蛋白酶体和自噬途径消除它们。我们的研究结合果蝇遗传学和细胞生物学有助于理解PINK 1和Parkin介导的线粒体调控的分子机制以及PINK 1-Parkin通路缺陷导致PD神经变性的病理机制。

项目成果

Parkinson's disease-associated kinase PINK1 regulates Miro protein level and axonal transport of mitochondria.

• DOI: 10.1371/journal.pgen.1002537
• 发表时间: 2012
• 期刊: PLoS genetics
• 影响因子: 4.5
• 作者: Liu S;Sawada T;Lee S;Yu W;Silverio G;Alapatt P;Millan I;Shen A;Saxton W;Kanao T;Takahashi R;Hattori N;Imai Y;Lu B
• 通讯作者: Lu B

The HECT-type ubiquitin ligase Huwe1/Mule mediates the stability of PINK1

HECT型泛素连接酶Huwe1/Mule介导PINK1的稳定性

• 发表时间: 2011
• 作者: 澤田知世;他
• 通讯作者: 他

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~

Dysregulation of microRNA-mediated translational repression is involved in neurodegeneration in a Drosophila model of Parkinson's disease

microRNA介导的翻译抑制失调与帕金森病果蝇模型中的神经变性有关

• 发表时间: 2011
• 期刊: Bulletin
• 作者: Imai;Y.
• 通讯作者: Y.

モデルショウジョウバエを用いた遺伝性若年性パーキンソン病の研究

果蝇模型研究遗传性早发型帕金森病

• 发表时间: 2011
• 作者: 平出桜;菅野直人;坪井博文;竪山真規;石山勝也;青木正志;永坂真也;今居 譲
• 通讯作者: 今居 譲