The Neglected Genes of ALS: Cytoskeletal Dynamics Impact Synaptic Degeneration in ALS.
The Neglected Genes of ALS: Cytoskeletal Dynamics Impact Synaptic Degeneration in ALS.
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DOI：
10.3389/fncel.2020.594975
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发表时间：
2020
影响因子：
5.3
通讯作者：
Durcan TM
中科院分区：
文献类型：
--
作者：
Castellanos-Montiel MJ;Chaineau M;Durcan TM
肌萎缩侧索硬化症（ALS）是一种选择性影响皮质、脑干和脊髓运动神经元（MN）的神经退行性疾病。有几个基因与ALS的家族性（fALS）和散发性（sALS）病例有关。在所有ALS相关基因中，已知直接影响细胞骨架动力学的一组基因（ALS 2、DCTN 1、PFN 1、KIF 5A、NF-L、NF-H、PRPH、SPAST和TUBA 4A）对于MN健康和存活具有高度重要性，因为MN是具有轴突的大型极化细胞，其长度可达1 m。特别是，细胞骨架动力学促进细胞器和分子在细胞内长轴突距离的运输，在突触维持中发挥关键作用。在过去的二十年中，大多数ALS相关基因影响细胞骨架动力学被确定，使其成为ALS研究的新领域。这篇综述的目的是提供ALS相关的细胞骨架基因的见解，并概述了最近的研究如何指向新的途径，可能会影响ALS。进一步的研究利用广泛的分析模型来寻找真正的命中，最新的技术，如CRIPSR/Cas9，人类诱导多能干细胞（iPSC）和轴突测序，以及开发更多的转基因动物模型可能有助于：区分真正作为疾病主要原因的变异与作为风险因素或疾病修饰因子的变异，确定两个或多个ALS相关基因在疾病发作和进展中的潜在相互作用，并增加我们对导致细胞骨架缺陷的分子机制的理解。总之，这些信息将给我们一个提示，在这个致命的疾病中，细胞骨架ALS相关基因的真实的贡献。
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that selectively affects motor neurons (MNs) of the cortex, brainstem, and spinal cord. Several genes have been linked to both familial (fALS) and sporadic (sALS) cases of ALS. Among all the ALS-related genes, a group of genes known to directly affect cytoskeletal dynamics (ALS2, DCTN1, PFN1, KIF5A, NF-L, NF-H, PRPH, SPAST, and TUBA4A) is of high importance for MN health and survival, considering that MNs are large polarized cells with axons that can reach up to 1 m in length. In particular, cytoskeletal dynamics facilitate the transport of organelles and molecules across the long axonal distances within the cell, playing a key role in synapse maintenance. The majority of ALS-related genes affecting cytoskeletal dynamics were identified within the past two decades, making it a new area to explore for ALS. The purpose of this review is to provide insights into ALS-associated cytoskeletal genes and outline how recent studies have pointed towards novel pathways that might be impacted in ALS. Further studies making use of extensive analysis models to look for true hits, the newest technologies such as CRIPSR/Cas9, human induced pluripotent stem cells (iPSCs) and axon sequencing, as well as the development of more transgenic animal models could potentially help to: differentiate the variants that truly act as a primary cause of the disease from the ones that act as risk factors or disease modifiers, identify potential interactions between two or more ALS-related genes in disease onset and progression and increase our understanding of the molecular mechanisms leading to cytoskeletal defects. Altogether, this information will give us a hint on the real contribution of the cytoskeletal ALS-related genes during this lethal disease.
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影响因子：
3.5
作者：
Fil D;DeLoach A;Yadav S;Alkam D;MacNicol M;Singh A;Compadre CM;Goellner JJ;O'Brien CA;Fahmi T;Basnakian AG;Calingasan NY;Klessner JL;Beal FM;Peters OM;Metterville J;Brown RH Jr;Ling KKY;Rigo F;Ozdinler PH;Kiaei M
通讯作者：
Kiaei M
影响因子：
5.2
作者：
Denton, Kyle R.;Lei, Ling;Grenier, Jeremy;Rodionov, Vladimir;Blackstone, Craig;Li, Xue-Jun
通讯作者：
Li, Xue-Jun
影响因子：
5.1
作者：
Chandran, Jayanth;Ding, Jinhui;Cai, Huaibin
通讯作者：
Cai, Huaibin
影响因子：
4.8
作者：
Brettle, Merryn;Stefen, Holly;Fath, Thomas
通讯作者：
Fath, Thomas
影响因子：
5.1
作者：
Geevasinga, N.;Menon, P.;Vucic, S.
通讯作者：
Vucic, S.