Pregnenolone and pregnenolone-methyl-ether rescue neuronal defects caused by dysfunctional CLIP170 in a neuronal model of CDKL5 Deficiency Disorder

Barbiero, Isabella; Peroni, Diana; P, Siniscalchi; Rusconi, Laura; Tramarin, Marco; Rosa, Roberta De; Motta, Paolo; Bianchi, Massimiliano; Kilstrup‐Nielsen, Charlotte

doi:10.1016/j.neuropharm.2019.107897

Cited by 15 publications

(35 citation statements)

References 44 publications

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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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Section: Therapymentioning

confidence: 99%

CDKL5 Deficiency Disorder—A Complex Epileptic Encephalopathy

Jakimiec¹,

Paprocka

Śmigiel

2020

Brain Sciences

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“…This is accompanied by a reduced capacity of MTs to penetrate the actin arcs and protrude into the peripheral domain [39]. CDKL5 deficiency reduces the association of CLIP170 to MTs in proliferating cells and in the axonal growth cone of Cdkl5 -KO neurons, which in both cases is accompanied by altered MT dynamics [9,40]. The binding of CLIP170 to MTs occurs when the protein is in its open active conformation whereas the intramolecular interaction between its terminal CAP-Gly domain and zinc-knuckle motifs causes a closed inactive conformation [41].…”

Section: Neuronal Cdkl5 Related Defectsmentioning

confidence: 99%

“…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].…”

Section: Neuronal Cdkl5 Related Defectsmentioning

confidence: 99%

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

Barbiero

Rosa

Kilstrup‐Nielsen

2019

IJMS

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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.

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“…A previous study showed that CDKL5 deficiency interferes with the IQGAP1/cytoplasmic linker protein of 170 kDa (CLIP170)/Rac1 ternary complex formation and negatively influences the microtubule binding of CLIP170 [63]. Furthermore, knockdown of CDKL5 halted cone growth, suppressed axon elongation, and decreased polarised neurons [63,119]. The neuroactive steroid pregnenolone synthetic derivative, pregnenolone-methyl-ether (also known as 3β-methoxy-pregnenolone), has been found to rescue morphological defects in CDKL5-deficient neurons by restoring the microtubule association of CLIP170 [63,119].…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, knockdown of CDKL5 halted cone growth, suppressed axon elongation, and decreased polarised neurons [63,119]. The neuroactive steroid pregnenolone synthetic derivative, pregnenolone-methyl-ether (also known as 3β-methoxy-pregnenolone), has been found to rescue morphological defects in CDKL5-deficient neurons by restoring the microtubule association of CLIP170 [63,119]. Therefore, targeting the association between CDKL5 and microtubules may be an effective therapeutic strategy.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2020

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Cyclin-dependent kinase-like 5 (CDKL5, also known as STK9) is a serine/threonine protein kinase originally identified in 1998 during a transcriptional mapping project of the human X chromosome. Thereafter, a mutation in CDKL5 was reported in individuals with the atypical Rett syndrome, a neurodevelopmental disorder, suggesting that CDKL5 plays an important regulatory role in neuronal function. The disease associated with CDKL5 mutation has recently been recognised as CDKL5 deficiency disorder (CDD) and has been distinguished from the Rett syndrome owing to its symptomatic manifestation. Because CDKL5 mutations identified in patients with CDD cause enzymatic loss of function, CDKL5 catalytic activity is likely strongly associated with the disease. Consequently, the exploration of CDKL5 substrate characteristics and regulatory mechanisms of its catalytic activity are important for identifying therapeutic target molecules and developing new treatment. In this review, we summarise recent findings on the phosphorylation of CDKL5 substrates and the mechanisms of CDKL5 phosphorylation and dephosphorylation. We also discuss the relationship between changes in the phosphorylation signalling pathways and the Cdkl5 knockout mouse phenotype and consider future prospects for the treatment of mental and neurological disease associated with CDKL5 mutations.

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Pregnenolone and pregnenolone-methyl-ether rescue neuronal defects caused by dysfunctional CLIP170 in a neuronal model of CDKL5 Deficiency Disorder

Cited by 15 publications

References 44 publications

CDKL5 Deficiency Disorder—A Complex Epileptic Encephalopathy

CDKL5 Deficiency Disorder—A Complex Epileptic Encephalopathy

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

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

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