Lemur tyrosine kinase-2 and axonal transport of cdk5/p35 and protein phosphatase-1

狐猴酪氨酸激酶 2 和 cdk5/p35 和蛋白磷酸酶 1 的轴突运输

• 批准号: BB/L019299/1
• 负责人: Christopher Miller
• 金额: $ 46.99万
• 依托单位: King's College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2014
• 资助国家: 英国
• 起止时间: 2014 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FL019299%2F1
• 关键词: Lemur; tyrosine; kinase; axonal; transport

The abilities of our brains to compute information is linked to the numbers of connections that individual brain neuron cells make with one another. These connections are termed synapses and it is estimated that a human brain contains 100-500 trillion synapses. Loss of synapses occurs as we age and pathogenic synaptic loss is believed be the underlying cause of dementia in Alzheimer's disease. The mechanisms by which synapses are lost in ageing and disease are not properly understood but one suggestion is that it involves, at least in part, defects to the delivery of essential proteins and other components to the synapse. Most synaptic proteins are synthesized in a different part of the neuron cell and so have to be transported to synapses. One type of transport is termed axonal transport and this involves moving protein cargoes through the long axon processes of neurons. This movement involves "molecular motor proteins" and these run on rails called microtubules and utilize a fuel called ATP. Axonal transport is therefore like a train journey with a motor or engine that requires a fuel and runs on rails. Cyclin dependent kinase-5/p35 (Cdk5/p35) and protein phosphatase-1 (PP1) are two major protein complexes that perform a number of essential functions in the synapse. Moreover, disruption to cdk5/p35 and PP1 functions are linked to Alzheimer's and other neurodegenerative diseases. However, the mechanisms by which these important proteins are transported to the synapse are not known. We have shown that cdk5/p35 and PP1 both bind to another protein called lemur tyrosine kinase-2 (LMTK2) and that LMTK2 attaches to a molecular motor called kinesin-1. Thus, cdk5/p35 and PP1 may be transported to synapses on kinesin-1 motors via their attachment to LMTK2. The Aim of this project is to test this possibility. The objectives are:-1. To finalise our studies demonstrating that LMTK2 scaffolds cdk5/p35 and PP1 to KLCs.2. To properly characterise axonal transport of LMTK2.3. To study the role of LMTK2 on axonal transport of cdk5/p35 and PP1. 4. To investigate the mechanisms that regulate axonal transport of the LMTK2-cdk5/p35-PP1 complexThe study will provide important information on fundamental neurophysiological processes. In addition, since damage to axonal transport and to cdk5/p35 and PP1 synaptic functions are all seen in Alzheimer's and related diseases, the work may reveal new targets for therapeutic intervention for these disorders.

我们大脑计算信息的能力与单个脑神经细胞之间的连接数量有关。这些连接被称为突触，据估计，人脑中有100-500万亿个突触。突触的丧失随着年龄的增长而发生，致病性突触丧失被认为是阿尔茨海默病中痴呆的潜在原因。突触在衰老和疾病中丧失的机制尚不清楚，但有一种说法认为，至少在一定程度上，这与向突触输送必需蛋白质和其他成分的缺陷有关。大多数突触蛋白是在神经元细胞的不同部分合成的，因此必须被运送到突触。一种类型的运输被称为轴突运输，它涉及通过神经元的长轴突过程移动蛋白质货物。这种运动涉及到“分子运动蛋白”，它们在被称为微管的轨道上运行，并利用一种被称为ATP的燃料。因此，轴突运输就像一列有马达或发动机的火车，需要燃料并在轨道上运行。细胞周期蛋白依赖性激酶-5/p35 （Cdk5/p35）和蛋白磷酸酶-1 （PP1）是两个主要的蛋白复合物，在突触中执行许多基本功能。此外，cdk5/p35和PP1功能的破坏与阿尔茨海默病和其他神经退行性疾病有关。然而，这些重要的蛋白质被运送到突触的机制尚不清楚。我们已经证明cdk5/p35和PP1都与另一种叫做狐猴酪氨酸激酶-2 （LMTK2）的蛋白质结合，LMTK2附着在一个叫做激酶-1的分子马达上。因此，cdk5/p35和PP1可能通过附着在LMTK2上的运动蛋白-1马达被转运到突触。这个项目的目的就是测试这种可能性。目标是：-1。为了完成我们的研究，证明LMTK2可以将cdk5/p35和PP1支架到KLCs.2。正确表征LMTK2.3的轴突转运。研究LMTK2在cdk5/p35和PP1轴突转运中的作用。4. 研究调节LMTK2-cdk5/p35-PP1复合物轴突转运的机制，将为神经生理基础过程提供重要信息。此外，由于轴突运输和cdk5/p35和PP1突触功能的损伤都在阿尔茨海默病和相关疾病中发现，这项工作可能为这些疾病的治疗干预揭示新的靶点。

项目成果

There's Something Wrong with my MAM; the ER-Mitochondria Axis and Neurodegenerative Diseases.

• DOI: 10.1016/j.tins.2016.01.008
• 发表时间: 2016-03
• 期刊: Trends in neurosciences
• 影响因子: 15.9
• 作者: Paillusson S;Stoica R;Gomez-Suaga P;Lau DHW;Mueller S;Miller T;Miller CCJ
• 通讯作者: Miller CCJ

The ER-Mitochondria Tethering Complex VAPB-PTPIP51 Regulates Autophagy.

• DOI: 10.1016/j.cub.2016.12.038
• 发表时间: 2017-02-06
• 期刊: Current biology : CB
• 作者: Gomez-Suaga P;Paillusson S;Stoica R;Noble W;Hanger DP;Miller CCJ
• 通讯作者: Miller CCJ

Biological function of Lemur tyrosine kinase 2 (LMTK2): implications in neurodegeneration.

• DOI: 10.1186/s13041-018-0363-x
• 发表时间: 2018-04-10
• 期刊: Molecular brain
• 影响因子: 3.6
• 作者: Bencze J;Mórotz GM;Seo W;Bencs V;Kálmán J;Miller CCJ;Hortobágyi T
• 通讯作者: Hortobágyi T

A revised nomenclature for the lemur family of protein kinases.

• DOI: 10.1038/s42003-023-05671-8
• 发表时间: 2024-01-08
• 期刊: COMMUNICATIONS BIOLOGY
• 影响因子: 5.9
• 作者: Morotz, Gabor M.;Bradbury, Neil A.;Caluseriu, Oana;Hisanaga, Shin-ichi;Miller, Christopher C. J.;Swiatecka-Urban, Agnieszka;Lenz, Heinz-Josef;Moss, Stephen J.;Giamas, Georgios
• 通讯作者: Giamas, Georgios

Disruption of ER-mitochondria signalling in fronto-temporal dementia and related amyotrophic lateral sclerosis.

• DOI: 10.1038/s41419-017-0022-7
• 发表时间: 2018-02-28
• 期刊: Cell death & disease
• 影响因子: 9
• 作者: Lau DHW;Hartopp N;Welsh NJ;Mueller S;Glennon EB;Mórotz GM;Annibali A;Gomez-Suaga P;Stoica R;Paillusson S;Miller CCJ
• 通讯作者: Miller CCJ