Microtubules: A Key to Understand and Correct Neuronal Defects in CDKL5 Deficiency Disorder?

Abstract

CDKL5 deficiency disorder (CDD) is a severe neurodevelopmental encephalopathy caused by mutations in the X-linked CDKL5 gene that encodes a serine/threonine kinase. CDD is characterised by the early onset of seizures and impaired cognitive and motor skills. Loss of CDKL5 in vitro and in vivo affects neuronal morphology at early and late stages of maturation, suggesting a link between CDKL5 and the neuronal cytoskeleton. Recently, various microtubule (MT)-binding proteins have been identified as interactors of CDKL5, indicating that its roles converge on regulating MT functioning. MTs are dynamic structures that are important for neuronal morphology, migration and polarity. The delicate control of MT dynamics is fundamental for proper neuronal functions, as evidenced by the fact that aberrant MT dynamics are involved in various neurological disorders. In this review, we highlight the link between CDKL5 and MTs, discussing how CDKL5 deficiency may lead to deranged neuronal functions through aberrant MT dynamics. Finally, we discuss whether the regulation of MT dynamics through microtubule-targeting agents may represent a novel strategy for future pharmacological approaches in the CDD field.

Target-agnostic discovery of Rett Syndrome therapeutics by coupling computational network analysis and CRISPR-enabled in vivo disease modeling

“…As these observations also aligned with results of prior studies of HDAC6 acetylation of tubulin in cells of Rett patients 39, 40 and microtubule modulation in closely-related CDKL5 deficiency disorder 41 , we analyzed tadpole tissues for α-tubulin acetylation and observed bidirectional shifts in acetylation patterns depending on the tissue type. For example, α-tubulin was significantly hypoacetylated in neurons in sections of the midbrain and in olfactory bulb multi-ciliated cells that showed MeCP2 knockdown ( Supplementary Fig.…”

Expansion of the phenotypic spectrum of de novo missense variants in kinesin family member 1A ( KIF1A )

“…There is clear evidence that the RTT‐associated genes MECP2 and CDKL5 regulate microtubule stability and neuronal transport, and that pathogenic mutations in those genes disrupt microtubule dynamics (Barbiero, De Rosa, & Kilstrup‐Nielsen, 2019; Delepine, Nectoux, Bahi‐Buisson, Chelly, & Bienvenu, 2013; Gold, Lacina, Cantrill, & Christodoulou, 2015). Microtubules are highly dynamic structures that are critical for maintaining correct neuronal architecture and for the transport of cargos via motor proteins such as kinesins (KIFs) and dynein (Kevenaar & Hoogenraad, 2015).…”

Mispatterned motile cilia beating causes flow blockage in the epileptic brain

“…This involved perturbation in the highly interconnected cilia anchoring rootelin-containing meshworks. The homologous meshwork in the Xenopus epidermis has been shown to regulate the cellular patterning of basal body spacing and cilia polarity essential for metachronal synchrony of ciliary beating mediating epidermal mucus transport (20). In the v3V ependyma, a similar basal body anchoring meshwork was observed with rootelin fibers projecting towards the cell surface.…”

“…Cilia length, polarity and coordinated motion are modulated by actin dynamics (18,19), and both Cdkl5 and Yes1 are known to regulate the remodeling of actin (20,21). We conducted confocal microscopy to examine this ciliary rootlet meshwork using antibodies to γ-tubulin to visualize the basal bodies and rootletin antibody to visualize the meshwork.…”