Wang Hsin-Pei, Singh Shekhar, Wong Lee-Chin, Hsu Chia-Jui, Li Shih-Chi, Lee Shyh-Jye, Lee Chia-Hwa, Lee Wang-Tso
Department of Pediatrics, National Taiwan University Hospital, Yunlin Branch, Yunlin, 970, Taiwan.
National Taiwan University College of Medicine Graduate Institute of Clinical Medicine, Taipei, 100, Taiwan.
Mol Neurobiol. 2025 May 10. doi: 10.1007/s12035-025-05016-y.
AGTPBP1 regulates microtubule stabilization through post-translational modification of alpha-tubulin. Mutations in the AGTPBP1 gene are associated with clinical phenotypes such as early postnatal cerebellar atrophy, ataxia, spasticity, and dystonia, highlighting its critical roles in both neurodevelopment and neurodegeneration. However, how AGTPBP1 affects neurite development and its function in dopaminergic neurons remains unclear. To investigate the role of AGTPBP1, we utilized both in vitro AGTPBP1 knockout (KO) cell models and zebrafish models. Our findings reveal that AGTPBP1 KO in cells leads to excessive neurite outgrowth and significantly increases expression of collapsin response mediator protein 2 (CRMP2). Additionally, AGTPBP1 KO results in mitochondrial dysfunction and a hyperdopaminergic state in differentiated neurons. In zebrafish, knockdown of AGTPBP1 caused reduced brain volume and impaired swimming behavior, indicating disrupted neurodevelopment and motor function. Given CRMP2's involvement in both cytoskeletal dynamics and mitochondrial activity, we tested lacosamide, a drug known to modulate CRMP2 expression and phosphorylation. Lacosamide treatment in vitro improved cell morphology and restored mitochondrial function, while in vivo, it rescued brain volume deficits and enhanced swimming performance in AGTPBP1-deficient zebrafish. In conclusion, AGTPBP1 knockout impairs neuronal differentiation, induces mitochondrial dysfunction, increases oxidative stress, and promotes a hyperdopaminergic state. Our study suggests that elevated CRMP2 expression may underlie the pathophysiology of cerebellar degeneration in AGTPBP1-related disorders. Targeting CRMP2 with lacosamide represents a promising therapeutic strategy for mitigating AGTPBP1-mediated neurodegeneration.
AGTPBP1通过对α-微管蛋白的翻译后修饰来调节微管的稳定性。AGTPBP1基因的突变与出生后早期小脑萎缩、共济失调、痉挛和肌张力障碍等临床表型相关，突出了其在神经发育和神经退行性变中的关键作用。然而，AGTPBP1如何影响神经突发育及其在多巴胺能神经元中的功能仍不清楚。为了研究AGTPBP1的作用，我们使用了体外AGTPBP1基因敲除（KO）细胞模型和斑马鱼模型。我们的研究结果表明，细胞中的AGTPBP1基因敲除会导致神经突过度生长，并显著增加塌陷反应介导蛋白2（CRMP2）的表达。此外，AGTPBP1基因敲除会导致分化神经元中的线粒体功能障碍和高多巴胺能状态。在斑马鱼中，AGTPBP1的敲低导致脑容量减少和游泳行为受损，表明神经发育和运动功能受到破坏。鉴于CRMP2参与细胞骨架动力学和线粒体活动，我们测试了拉科酰胺，一种已知可调节CRMP2表达和磷酸化的药物。体外拉科酰胺治疗改善了细胞形态并恢复了线粒体功能，而在体内，它挽救了AGTPBP1缺陷斑马鱼的脑容量缺陷并增强了游泳性能。总之，AGTPBP1基因敲除会损害神经元分化，诱导线粒体功能障碍，增加氧化应激，并促进高多巴胺能状态。我们的研究表明，CRMP2表达升高可能是AGTPBP1相关疾病中小脑变性病理生理学的基础。用拉科酰胺靶向CRMP2是减轻AGTPBP1介导的神经退行性变的一种有前景的治疗策略。
