Lacosamide Is a Novel Drug That Improves AGTPBP1 Knockout-Mediated Impairment of Neuronal and Dopaminergic Function.

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.