Binding and transport of SFPQ-RNA granules by KIF5A/KLC1 motors promotes axon survival.
Binding and transport of SFPQ-RNA granules by KIF5A/KLC1 motors promotes axon survival.
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DOI：
10.1083/jcb.202005051
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发表时间：
2021-01-04
期刊：
影响因子：
--
通讯作者：
Segal RA
中科院分区：
文献类型：
--
作者：
Fukuda Y;Pazyra-Murphy MF;Silagi ES;Tasdemir-Yilmaz OE;Li Y;Rose L;Yeoh ZC;Vangos NE;Geffken EA;Seo HS;Adelmant G;Bird GH;Walensky LD;Marto JA;Dhe-Paganon S;Segal RA
Fukuda等人。证明RNA结合蛋白SFPQ优先由KIF5A运输，而不是Kinesin-1家族的其他马达。KIF5A对SPFQ的轴突转运缺陷导致轴突变性，从而为与KIF5A基因相关的神经系统疾病的特异性提供了机制上的理解。复杂的神经回路需要长轴突形成稳定的连接。为了维持这些功能回路，快速运输将RNA运送到远端轴突，在那里它们进行局部翻译。然而，使RNA颗粒能够长距离运输的机制尚不清楚。在这里，我们证明了包含RNA和RNA结合蛋白(RBP)SFPQ的复合体选择性地与包含接头KLC1和马达KIF5A的四聚体Kinesin相互作用。我们发现SFPQ与KIF5A/KLC1马达复合体的结合是轴突生存所必需的，并受到导致Charcot-Marie Tooth(CMT)病的KIF5A突变的影响。此外，在CMT模型中，不需要局部翻译SFPQ结合蛋白的治疗方法可以防止轴突变性。总之，这些观察表明，KIF5A介导的SFPQ-RNA颗粒运输可能是KIF5A相关神经疾病中的一个关键功能障碍，而替代轴突翻译蛋白是治疗轴突退行性疾病的一种方法。
Fukuda et al. demonstrate that the RNA-binding protein SFPQ is preferentially transported by KIF5A rather than other motors of the kinesin-1 family. Defective axonal transport of SPFQ by KIF5A leads to axon degeneration and therefore provides a mechanistic understanding of specificity for neurologic diseases linked to the KIF5A gene. Complex neural circuitry requires stable connections formed by lengthy axons. To maintain these functional circuits, fast transport delivers RNAs to distal axons where they undergo local translation. However, the mechanism that enables long-distance transport of RNA granules is not yet understood. Here, we demonstrate that a complex containing RNA and the RNA-binding protein (RBP) SFPQ interacts selectively with a tetrameric kinesin containing the adaptor KLC1 and the motor KIF5A. We show that the binding of SFPQ to the KIF5A/KLC1 motor complex is required for axon survival and is impacted by KIF5A mutations that cause Charcot-Marie Tooth (CMT) disease. Moreover, therapeutic approaches that bypass the need for local translation of SFPQ-bound proteins prevent axon degeneration in CMT models. Collectively, these observations indicate that KIF5A-mediated SFPQ-RNA granule transport may be a key function disrupted in KIF5A-linked neurologic diseases and that replacing axonally translated proteins serves as a therapeutic approach to axonal degenerative disorders.
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DOI：
10.1093/brain/awx370
发表时间：
2018-03-01
期刊：
Brain : a journal of neurology
影响因子：
--
作者：
Brenner D;Yilmaz R;Müller K;Grehl T;Petri S;Meyer T;Grosskreutz J;Weydt P;Ruf W;Neuwirth C;Weber M;Pinto S;Claeys KG;Schrank B;Jordan B;Knehr A;Günther K;Hübers A;Zeller D;Kubisch C;Jablonka S;Sendtner M;Klopstock T;de Carvalho M;Sperfeld A;Borck G;Volk AE;Dorst J;Weis J;Otto M;Schuster J;Del Tredici K;Braak H;Danzer KM;Freischmidt A;Meitinger T;Strom TM;Ludolph AC;Andersen PM;Weishaupt JH;German ALS network MND-NET
通讯作者：
German ALS network MND-NET
影响因子：
4.5
作者：
Füger P;Sreekumar V;Schüle R;Kern JV;Stanchev DT;Schneider CD;Karle KN;Daub KJ;Siegert VK;Flötenmeyer M;Schwarz H;Schöls L;Rasse TM
通讯作者：
Rasse TM
DOI：
10.1107/s2053230x19006599
发表时间：
2019-06-01
影响因子：
0.9
作者：
Hewage, Thushara Welwelwela;Caria, Sofia;Lee, Mihwa
通讯作者：
Lee, Mihwa
影响因子：
16.2
作者：
Jacobson, C;Schnapp, B;Banker, GA
通讯作者：
Banker, GA
影响因子：
16
作者：
Barclay, Lauren A.;Wales, Thomas E.;Garner, Thomas P.;Wachter, Franziska;Lee, Susan;Guerra, Rachel M.;Stewart, Michelle L.;Braun, Craig R.;Bird, Gregory H.;Gavathiotis, Evripidis;Engen, John R.;Walensky, Loren D.
通讯作者：
Walensky, Loren D.