Twellsieck Björn, Boecker C Alexander
Department of Neurology, University Medical Center Goettingen, 37077 Goettingen, Germany.
Biochem J. 2025 Jun 25;482(13):BCJ20253133. doi: 10.1042/BCJ20253133.
Axonal transport is crucial for neuronal health and function, facilitating the delivery of newly synthesized material from the soma via anterograde transport and the removal of aged proteins and damaged organelles for degradation via retrograde transport. Emerging evidence links Parkinson's disease (PD)-causing mutations in the leucine-rich repeat kinase 2 (LRRK2) gene to dysfunctional axonal transport. Pathogenic LRRK2 mutations induce increased LRRK2 kinase activity, leading to the hyperphosphorylation of RAB proteins, which are key regulators of intracellular trafficking and transport. Here, we review the current literature on how LRRK2 affects the axonal transport of different cargoes, focusing on synaptic vesicle precursors, mitochondria, and autophagosomes. We further discuss how LRRK2 influences cytoskeletal dynamics and how it affects vesicle trafficking at the Golgi, which may indirectly contribute to its effect on axonal transport. This review summarizes our current understanding of how pathogenic LRRK2 hyperactivation disrupts axonal transport and how this may be linked to the neurodegeneration of PD.
轴突运输对神经元的健康和功能至关重要，它通过顺行运输促进新合成物质从胞体的递送，并通过逆行运输清除老化蛋白质和受损细胞器以进行降解。新出现的证据将帕金森病（PD）相关的富含亮氨酸重复激酶2（LRRK2）基因突变与轴突运输功能障碍联系起来。致病性LRRK2突变会导致LRRK2激酶活性增加，导致RAB蛋白过度磷酸化，而RAB蛋白是细胞内运输和转运的关键调节因子。在这里，我们综述了当前关于LRRK2如何影响不同货物轴突运输的文献，重点关注突触小泡前体、线粒体和自噬体。我们进一步讨论LRRK2如何影响细胞骨架动力学以及它如何影响高尔基体处的囊泡运输，这可能间接导致其对轴突运输的影响。本综述总结了我们目前对致病性LRRK2过度激活如何破坏轴突运输以及这可能如何与PD的神经退行性变相关联的理解。
