The neurosteroid pregnenolone reverts microtubule derangement induced by the loss of a functional CDKL5-IQGAP1 complex

Barbiero, Isabella; Peroni, Diana; Tramarin, Marco; Chandola, Chetan; Rusconi, Laura; Landsberger, Nicoletta; Kilstrup‐Nielsen, Charlotte

doi:10.1093/hmg/ddx237

Cited by 31 publications

(41 citation statements)

References 38 publications

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“…The way in which CDKL5 deficiency affects neuronal maturation is starting to be defined progressively with the identification of some of the molecular mechanisms underlying CDKL5 functions. CDKL5 forms a complex with PSD‐95 and NGL‐1 at the spine level to regulate spine morphology and maintenance , and with IQ domain‐containing GTPase‐activating protein 1 (IQGAP1) and MAP1S to regulate microtubule dynamics and stability . Although data clearly suggest that CDKL5 is important for correct neuronal maturation , the role of CDKL5 in the maintenance of neuron survival has been poorly investigated.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2019

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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

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Section: Introductionmentioning

confidence: 99%

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

et al. 2019

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“…Recent findings indicate that CDKL5 may regulate dendritic spines not only by interacting with PDS-95 but also by directly binding with microtubule-associated proteins such as the IQ Motif Containing GTPase Activating Protein 1 (IQGAP1) (Barbiero et al, 2017) and MAP1S, EB2 and ARHGEF2 (Baltussen et al, 2018). Furthermore, CDKL5 might regulate dendritic spines composition and function by controlling the transcriptional levels of key components of dendritic spines.…”

Section: Discussionmentioning

confidence: 99%

Structural Bases of Atypical Whisker Responses in a Mouse Model of CDKL5 Deficiency Disorder

et al. 2020

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Highlights • CDKL5 deficiency disrupts the synaptic organization of thalamo-cortical (TC) and cortico-cortical (CC) connections in the barrel cortex (BC) • CDKL5 deficiency leads to BC hypoactivation • CDKL5 deficiency causes atypical whisker-mediated behavioural responses • CDKL5 deficiency does not prevent TC circuitry to undergo experience-dependent structural plasticity • Enhanced sensory stimulation restores cortical connectivity, BC activation levels and whisker-related behavioural responses ABSTRACT Mutations in the CDKL5 (cyclin-dependent kinase-like 5) gene cause CDKL5 Deficiency Disorder (CDD), a severe neurodevelopmental syndrome where patients exhibit early-onset seizures, intellectual disability, stereotypies, limited or absent speech, autism-like symptoms and sensory impairments. Mounting evidences indicate that disrupted sensory perception and processing represent core signs also in mouse models of CDD, however we have very limited knowledge on their underlying causes. In this study, we investigated how CDKL5 deficiency affects synaptic organization and experience-dependent plasticity in the thalamo-cortical (TC) pathway carrying whisker-related tactile information to the barrel cortex (BC). By using synapse-specific antibodies and confocal microscopy, we found that Cdkl5-KO mice display a lower density of TC synapses in the BC that was paralleled by a reduction of cortico-cortical (CC) connections compared to wild-type mice. These synaptic defects were accompanied by reduced BC activation, as shown by a robust decrease of c-fos immunostaining, and atypical behavioural responses to whisker-mediated tactile stimulation. Notably, a two-day paradigm of enriched whisker stimulation rescued both number and configuration of TC and CC synapses in Cdkl5-KO mice, and restored cortical activity as well as behavioural responses to control levels. Our findings disclose an important role of CDKL5 in controlling the organization and experience-induced modifications of excitatory connections in the BC and indicate how mutations of CDKL5 produce failures in higher-order processing of somatosensory stimuli.

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“…Studies have been conducted to develop precise therapy based on the biological, metabolic and genetic basis of CDD. These studies include the use of NMDA (N-methyl-D-aspartate) receptor modulators [50]; allopregnanolone (a neurosteroid that restores normal microtubule morphology) [51,52]; tianeptine, which is an antidepressant affecting AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptors [53]; or insulin-like growth factor IGF-1 activating the Akt/mTOR pathway [54]. Hopes are related to gene therapy as a causal treatment for disorders due to CDKL5 mutations.…”

Section: Therapymentioning

confidence: 99%

CDKL5 Deficiency Disorder—A Complex Epileptic Encephalopathy

Jakimiec¹,

Paprocka

Śmigiel

2020

Brain Sciences

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CDKL5 deficiency disorder (CDD) is a complex of clinical symptoms resulting from the presence of non-functional CDKL5 protein, i.e., serine-threonine kinase (previously referred to as STK9), or its complete absence. The clinical picture is characterized by epileptic seizures (that start within the first three months of life and most often do not respond to pharmacological treatment), epileptic encephalopathy secondary to seizures, and retardation of psychomotor development, which are often observed already in the first months of life. Due to the fact that CDKL5 is located on the X chromosome, the prevalence of CDD among women is four times higher than in men. However, the course is usually more severe among male patients. Recently, many clinical centers have analyzed this condition and provided knowledge on the function of CDKL5 protein, the natural history of the disease, therapeutic options, and their effectiveness and prognosis. The International CDKL5 Disorder Database was established in 2012, which focuses its activity on expanding knowledge related to this condition and disseminating such knowledge to the families of patients.

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The neurosteroid pregnenolone reverts microtubule derangement induced by the loss of a functional CDKL5-IQGAP1 complex

Cited by 31 publications

References 38 publications

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

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

Structural Bases of Atypical Whisker Responses in a Mouse Model of CDKL5 Deficiency Disorder

CDKL5 Deficiency Disorder—A Complex Epileptic Encephalopathy

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