Increased DNA Damage and Apoptosis in CDKL5-Deficient Neurons

Loi, Manuela; Trazzi, Stefania; Fuchs, Claudia; Galvani, Giuseppe; Medici, Giorgio; Gennaccaro, Laura; Tassinari, Marianna; Ciani, Elisabetta

doi:10.1007/s12035-020-01884-8

Cited by 20 publications

(44 citation statements)

References 69 publications

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“…As previously reported in male Cdkl5 KO mice [19,20], we found here that hippocampal neurons of heterozygous female Cdkl5 KO mice showed an increased vulnerability to excitotoxicity. In ammatory processes, including activation of microglia and production of proin ammatory cytokines, such as TNF-α, IL-1β, and IL-6, are associated with excitotoxic stimuli [59,60].…”

Section: Discussionsupporting

confidence: 91%

“…To investigate whether microglia over-activation has a causative role in the increased neuronal susceptibility to excitotoxic stress in Cdkl5 KO mice [19,20], we pre-treated Cdkl5 +/-mice for 7 days with Luteolin before NMDA (60mg/kg) intraperitoneal injection (Fig. 9A).…”

Section: Microglia Activation With Age In Cdkl5 +/-Micementioning

confidence: 99%

“…Cdkl5 KO mice showed a reduction in dendritic length of cortical and hippocampal pyramidal neurons [6,11,15,16] and changes in the maturation and stability of dendritic spines, as well as in the density of PSD-95 dendritic clusters in several brain structures [10,[15][16][17][18]. Interestingly, recent evidence has shown that CDKL5, in addition to neuronal maturation and dendritic outgrowth, also affects neuronal survival [11,19,20]. Cdkl5 KO mice are characterized by an increased rate of apoptotic cell death in the hippocampal dentate gyrus that causes a reduction in the nal number of granule neurons [11] and by accelerated neuronal senescence/death during aging [21].…”

Section: Introductionmentioning

confidence: 99%

“…Cdkl5 KO mice are characterized by an increased rate of apoptotic cell death in the hippocampal dentate gyrus that causes a reduction in the nal number of granule neurons [11] and by accelerated neuronal senescence/death during aging [21]. Moreover, hippocampal neurons of Cdkl5 KO mice exhibit increased susceptibility to neurotoxic/excitotoxic stress [19,20], indicating that absence of Cdkl5 increase neuronal vulnerability.…”

Section: Introductionmentioning

confidence: 99%

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Inhibition of Microglia Over-activation Restores Neuronal Survival in a Mouse Model of CDKL5 Deficiency Disorder

Galvani

Mottolese

Gennaccaro

et al. 2021

Preprint

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BackgroundCDKL5 Deficiency Disorder (CDD), a severe neurodevelopmental disorder characterized by early-onset epilepsy, intellectual disability, and autistic features, is caused by mutations in the CDKL5 gene. Evidence in animal models of CDD showed that absence of CDKL5 negatively affects neuronal survival, as well as neuronal maturation and dendritic outgrowth; however, knowledge of the substrates underlying these alterations is still limited. Neuro-inflammatory processes are known to contribute to neuronal dysfunction and death. Recent evidence shows a subclinical chronic inflammatory status in plasma from CDD patients. However, to date, it is unknown whether a similar inflammatory status is present in the brain of CDD patients and, if so, whether this plays a causative or exacerbating role in the pathophysiology of CDD. MethodsWe evaluated microglia activation using AIF-1 immunofluorescence, proinflammatory cytokine expression and signaling in the brain of a mouse model of CDD, the Cdkl5 KO mouse, which is characterized by an impaired survival of hippocampal neurons that worsens with age. Hippocampal neuron survival was determined by DCX, NeuN and cleaved caspase-3 immunostaining in Cdkl5 KO mice treated with luteolin (10 mg/kg), a natural anti-inflammatory flavonoid. Since hippocampal neurons of Cdkl5 KO mice exhibit increased susceptibility to excitotoxic stress, we evaluated neuronal survival in Cdkl5 KO mice injected with NMDA (60 mg/kg) after a 7-day treatment with luteolin. ResultsWe found increased microglial activation in the brain of the Cdkl5 KO mouse. We found alterations in microglial cell morphology and number, increased levels of AIF-1 and proinflammatory cytokines, and activation of STAT3 signaling. Remarkably, treatment with luteolin recovers microglia alterations as well as neuronal survival and maturation in Cdkl5 KO mice, and prevents the increase in NMDA-induced cell death in the hippocampus. ConclusionsOur results suggest that neuro-inflammatory processes contribute to the pathogenesis of CDD and imply the potential usefulness of luteolin as a treatment option in CDD patients.

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Section: Discussionsupporting

confidence: 91%

Section: Microglia Activation With Age In Cdkl5 +/-Micementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Inhibition of Microglia Over-activation Restores Neuronal Survival in a Mouse Model of CDKL5 Deficiency Disorder

Galvani

Mottolese

Gennaccaro

et al. 2021

Preprint

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“…Recent evidence has highlighted the role of CDKL5 in neuronal survival [14,22,23]. It has been demonstrated that in the postnatal developing mouse hippocampus, loss of Cdkl5 increases the proliferation rate of neuronal precursors but causes the death of immature newborn neurons, thereby modulating the intricate balance between precursor proliferation and survival.…”

mentioning

confidence: 99%

Age-Related Cognitive and Motor Decline in a Mouse Model of CDKL5 Deficiency Disorder is Associated with Increased Neuronal Senescence and Death

Gennaccaro¹,

Fuchs²,

Loi³

et al. 2021

Aging and disease

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CDKL5 deficiency disorder (CDD) is a severe neurodevelopmental disease caused by mutations in the X-linked CDKL5 gene. Children affected by CDD display a clinical phenotype characterized by early-onset epilepsy, intellectual disability, motor impairment, and autistic-like features. Although the clinical aspects associated with CDKL5 mutations are well described in children, adults with CDD are still under-characterized. Similarly, most animal research has been carried out on young adult Cdkl5 knockout (KO) mice only. Since age represents a risk factor for the worsening of symptoms in many neurodevelopmental disorders, understanding age differences in the development of behavioral deficits is crucial in order to optimize the impact of therapeutic interventions. Here, we compared young adult Cdkl5 KO mice with middle-aged Cdkl5 KO mice, at a behavioral, neuroanatomical, and molecular level. We found an age-dependent decline in motor, cognitive, and social behaviors in Cdkl5 KO mice, as well as in breathing and sleep patterns. The behavioral decline in older Cdkl5 KO mice was not associated with a worsening of neuroanatomical alterations, such as decreased dendritic arborization or spine density, but was paralleled by decreased neuronal survival in different brain regions such as the hippocampus, cortex, and basal ganglia. Interestingly, we found increased β-galactosidase activity and DNA repair protein levels, γH2AX and XRCC5, in the brains of older Cdkl5 KO mice, which suggests that an absence of Cdkl5 accelerates neuronal senescence/death by triggering irreparable DNA damage. In summary, this work provides evidence that CDKL5 may play a fundamental role in neuronal survival during brain aging and suggests a possible worsening with age of the clinical picture in CDD patients.

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Novel CDKL5 targets identified in human iPSC-derived neurons

Massey,

Ang,

Davidson

et al. 2024

Cell. Mol. Life Sci.

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CDKL5 Deficiency Disorder (CDD) is a debilitating epileptic encephalopathy disorder affecting young children with no effective treatments. CDD is caused by pathogenic variants in Cyclin-Dependent Kinase-Like 5 (CDKL5), a protein kinase that regulates key phosphorylation events in neurons. For therapeutic intervention, it is essential to understand molecular pathways and phosphorylation targets of CDKL5. Using an unbiased phosphoproteomic approach we identified novel targets of CDKL5, including GTF2I, PPP1R35, GATAD2A and ZNF219 in human iPSC-derived neuronal cells. The phosphoserine residue in the target proteins lies in the CDKL5 consensus motif. We validated direct phosphorylation of GTF2I and PPP1R35 by CDKL5 using complementary approaches. GTF2I controls axon guidance, cell cycle and neurodevelopment by regulating expression of neuronal genes. PPP1R35 is critical for centriole elongation and cilia morphology, processes that are impaired in CDD. PPP1R35 interacts with CEP131, a known CDKL5 phospho-target. GATAD2A and ZNF219 belong to the Nucleosome Remodelling Deacetylase (NuRD) complex, which regulates neuronal activity-dependent genes and synaptic connectivity. In-depth knowledge of molecular pathways regulated by CDKL5 will allow a better understanding of druggable disease pathways to fast-track therapeutic development.

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Increased DNA Damage and Apoptosis in CDKL5-Deficient Neurons

Cited by 20 publications

References 69 publications

Inhibition of Microglia Over-activation Restores Neuronal Survival in a Mouse Model of CDKL5 Deficiency Disorder

Inhibition of Microglia Over-activation Restores Neuronal Survival in a Mouse Model of CDKL5 Deficiency Disorder

Age-Related Cognitive and Motor Decline in a Mouse Model of CDKL5 Deficiency Disorder is Associated with Increased Neuronal Senescence and Death

Novel CDKL5 targets identified in human iPSC-derived neurons

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Increased DNA Damage and Apoptosis in CDKL5-Deficient Neurons

Cited by 20 publications

References 69 publications

Inhibition of Microglia Over-activation Restores Neuronal Survival in a Mouse Model of CDKL5&nbsp;Deficiency Disorder

Inhibition of Microglia Over-activation Restores Neuronal Survival in a Mouse Model of CDKL5&nbsp;Deficiency Disorder

Age-Related Cognitive and Motor Decline in a Mouse Model of CDKL5 Deficiency Disorder is Associated with Increased Neuronal Senescence and Death

Novel CDKL5 targets identified in human iPSC-derived neurons

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Inhibition of Microglia Over-activation Restores Neuronal Survival in a Mouse Model of CDKL5 Deficiency Disorder

Inhibition of Microglia Over-activation Restores Neuronal Survival in a Mouse Model of CDKL5 Deficiency Disorder