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Mutations in the X-linked cyclin-dependent kinase-like 5 (CDKL5) gene are responsible for the onset of CDKL5 Deficiency Disorder (CDD), a neurological pathology characterised by severe infantile seizures, intellectual disability, impairment of gross motor skills, sleep and gastrointestinal disturbances. CDKL5 is a serine/threonine kinase the molecular network of which is not yet fully understood. Loss of CDKL5 both in vitro and in vivo leads to altered neuronal morphology including axon specification and outgrowth, dendritic arborisation and spine morphology suggesting a link between CDKL5 and the regulation of proper cytoskeleton functioning. Recently, we found that CDKL5 regulates the binding of CLIP170 to microtubules (MT). CLIP170 is a MT-plus end tracking protein (+TIP) that associates with MTs when present in its open, active conformation. Here we present evidence suggesting CLIP170 contributes to neuronal CDKL5-dependent defects and that it represents an important novel druggable target for CDD; indeed, CLIP170 is directly targeted by the neuroactive steroid pregnenolone (PREG), which induces the active conformation of the protein thus promoting MT-dynamics. We here show that PREG and a synthetic derivative pregnenolone-methyl-ether (PME) can restore the MT association of CLIP170 and revert morphological and molecular defects in Cdkl5-KO neurons at different stages of maturation. All together, these findings identify CLIP170 as possible novel druggable target for CDKL5 related disorders providing an intriguing prospective for future disease-modifying drug-based therapies.
This article was published in the following journal.
Pregnenolone and dehydroepiandrosterone (DHEA) are hydroxysteroids that serve as biosynthetic precursors for steroid hormones in human body. SULT2B1b has been reported to be critically involved in the...
The pregnenolone-progesterone-allopregnanolone pathway is receiving increasing attention in research on the role of neurosteroids in pathophysiology, particularly in stress-related and drug use disord...
Intact steroid hormone biosynthesis is essential for growth and development of the human fetus and embryo. In the present study, gas chromatography-mass spectrometry was employed to characterize the s...
Previous studies have uncovered a progestin-only contraceptive association with an increased risk of diabetes, but limited study has explored the relationship of endogenous progesterone and pregnenolo...
Translocator protein 18 kDa (TSPO) is located in the mitochondrial outer membrane and plays an important role in steroidogenesis and cell survival. In the central nervous system (CNS), its expressio...
Pregnenolone, an over-the-counter supplement, is a naturally occurring neurosteroid made in the adrenal glands and brain. Preclinical research suggests pregnenolone has antidepressant, cog...
Four-month trial of pregnenolone or placebo, as an additional medication, to treat negative symptoms and cognitive decline in schizophrenia. After four months the scores on the negative sy...
This is a pilot study of pregnenolone as an augmentation treatment for schizophrenia. The goal of this placebo-controlled study is to provide preliminary efficacy data for potential pregn...
The overall purpose of this study is to examine the effect of Pregnenolone (PREG) on the acute psychosis-like and cognitive effects of Delta-9-Tetrahydrocannabinol (THC). This will be test...
HYPOTHESIS: Pregnenolone administration will be associated with greater reduction in depressive symptom severity than placebo in women with current mMDD. STUDY AIMS: Primary...
A 21-carbon steroid, derived from CHOLESTEROL and found in steroid hormone-producing tissues. Pregnenolone is the precursor to GONADAL STEROID HORMONES and the adrenal CORTICOSTEROIDS.
A microsomal cytochrome P450 enzyme that catalyzes the 17-alpha-hydroxylation of progesterone or pregnenolone and subsequent cleavage of the residual two carbons at C17 in the presence of molecular oxygen and NADPH-FERRIHEMOPROTEIN REDUCTASE. This enzyme, encoded by CYP17 gene, generates precursors for glucocorticoid, androgen, and estrogen synthesis. Defects in CYP17 gene cause congenital adrenal hyperplasia (ADRENAL HYPERPLASIA, CONGENITAL) and abnormal sexual differentiation.
A catatoxic steroid and microsomal enzyme inducer having significant effects on the induction of cytochrome P450. It has also demonstrated the potential for protective capability against acetaminophen-induced liver damage.
The wide middle zone of the adrenal cortex. This zone produces a series of enzymes that convert PREGNENOLONE to cortisol (HYDROCORTISONE) via 17-ALPHA-HYDROXYPROGESTERONE.
The inner zone of the adrenal cortex. This zone produces the enzymes that convert PREGNENOLONE, a 21-carbon steroid, to 19-carbon steroids (DEHYDROEPIANDROSTERONE; and ANDROSTENEDIONE) via 17-ALPHA-HYDROXYPREGNENOLONE.
Bioinformatics is the application of computer software and hardware to the management of biological data to create useful information. Computers are used to gather, store, analyze and integrate biological and genetic information which can then be applied...
Sleep disorders disrupt sleep during the night, or cause sleepiness during the day, caused by physiological or psychological factors. The common ones include snoring and sleep apnea, insomnia, parasomnias, sleep paralysis, restless legs syndrome, circa...