CDKL5 deficiency predisposes neurons to cell death through the deregulation of SMAD3 signaling

Abstract

CDKL5 deficiency disorder (CDD) is a rare encephalopathy characterized by early onset epilepsy and severe intellectual disability. CDD is caused by mutations in the X-linked cyclin-dependent kinase-like 5 (CDKL5 ) gene, a member of a highly conserved family of serine-threonine kinases. Only a few physiological substrates of CDKL5 are currently known, which hampers the discovery of therapeutic strategies for CDD. Here, we show that SMAD3, a primary mediator of TGF-β action, is a direct phosphorylation target of CDKL5 and that CDKL5-dependent phosphorylation promotes SMAD3 protein stability. Importantly, we found that restoration of the SMAD3 signaling through TGF-β1 treatment normalized defective neuronal survival and maturation in Cdkl5 knockout (KO) neurons. Moreover, we demonstrate that Cdkl5 KO neurons are more vulnerable to neurotoxic/excitotoxic stimuli. In vivo treatment with TGF-β1 prevents increased NMDA-induced cell death in hippocampal neurons from Cdkl5 KO mice, suggesting an involvement of the SMAD3 signaling deregulation in the neuronal susceptibility to excitotoxic injury of Cdkl5 KO mice. Our finding reveals a new function for CDKL5 in maintaining neuronal survival that could have important implications for susceptibility to neurodegeneration in patients with CDD.Brain Pathology 29 (2019) 658-674

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

“…In primary low-density cultures of hippocampal neurons, CDKL5 controls axon specification and outgrowth [35,36]. Axon elongation relies on the formation of stable MTs in the axonal shaft.…”

“…CDKL5 deficiency was first shown, through silencing studies, to influence dendritic arborisation in vitro in primary cultures of rat cortical neurons and in vivo in migrating neurons derived from silenced neural progenitor cells [45]. Such defect has later been confirmed in cortical and hippocampal pyramidal neurons in Cdkl5 -KO brains [46,47,48] and reproduced in vitro in Cdkl5 -KO primary hippocampal neurons [36,40]. The penetrance of the phenotype in vitro may depend on the experimental conditions since contrasting data have been reported [11].…”

Rett Syndrome and CDKL5 Deficiency Disorder: From Bench to Clinic

“…CDKL5 has been implicated in neuronal survival via SMAD3 signaling suggesting neuronal susceptibility to excitotoxic injury in CDD [58]. Studies have shown that CDKL5 deficiency in primary hippocampal neurons leads to dysregulated expression of the alpha-amino-3-hydroxy-5-methyl-4-iso-xazole propionic acid receptors (AMPARs), particularly the GluA2 subunits [37].…”

Cyclin-Dependent Kinase-Like 5 (CDKL5): Possible Cellular Signalling Targets and Involvement in CDKL5 Deficiency Disorder

“…In 2019, Fuchs et al [77] found that CDKL5 phosphorylates SMAD3 in vitro. SMAD3 is a transcription factor that plays a central role in the neuronal function mediated by transforming growth factor-β signalling.…”

“…SMAD3 is a transcription factor that plays a central role in the neuronal function mediated by transforming growth factor-β signalling. The authors showed that protein levels of SMAD3 are reduced in the cortex and hippocampus of Cdkl5-knockout mouse [77]. It is therefore presumed that phosphorylation of SMAD3 regulates its protein levels.…”