CDKL5 regulates the initiation of retrograde axonal transport through CLIP170-dynactin complex formation.

Cyclin-dependent kinase-like 5 (CDKL5) is a serine-threonine kinase implicated in regulating microtubule (MT) dynamics. Mutations in CDKL5 are associated with a rare neurodevelopmental disease called CDKL5 deficiency disorder (CDD), which is characterized by early-onset seizures and intellectual disabilities. Microtubule (MT)-related functions of CDKL5 are in part correlated with its interaction with MT-associated proteins, such as CAP-Gly domain-containing linker protein 1 [CLIP1; also known as cytoplasmic linker protein 170 alpha-2 (CLIP170)]. CLIP170 is a MT plus-end tracking protein that, once activated, can bind MTs and other proteins, favoring MT dynamics. Importantly, we have previously shown that CLIP170 is inactive in the absence of CDKL5, thus hindering MT functions. One of the best-characterized interactors of CLIP170 is dynactin, a multisubunit complex that binds the motor protein dynein. In particular, in neurons, active CLIP170 localizes to MTs in the axonal periphery, where it serves as a docking site for the interaction with dynactin, which in turn recruits dynein and various cargos, favoring the initiation of retrograde transport toward the neuronal soma. Here, we demonstrated that CLIP170-dynactin complex formation is impaired in the absence of CDKL5, thus leading to defective retrograde cargo trafficking. Overall, our findings expand the knowledge on the molecular mechanisms underlying neuronal transport and provide novel information regarding the etiopathogenesis of CDD.