Modulation of Rho GTPases rescues brain mitochondrial dysfunction, cognitive deficits and aberrant synaptic plasticity in female mice modeling Rett syndrome

Filippis, Bianca De; Valenti, Daniela; Chiodi, Valentina; Ferrante, Antonella; Bari, Lidia de; Fiorentini, Carla; Domenici, Maria Rosaria; Ricceri, Laura; Vacca, Rosa Anna; Fabbri, Alessia; Laviola, Giovanni

doi:10.1016/j.euroneuro.2015.03.012

Cited by 42 publications

(67 citation statements)

References 49 publications

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“…The absence of Mecp2 abolished transcriptional regulation of both, Ryr3 and p250GAP , suggesting that Mecp2 contributes to experience dependent plasticity through Ryr3 -direct and p250GAP-indirect regulation. Interestingly, it was shown that activation of Rho GTPases rescues neurobehavioral abnormalities displayed by Mecp2-308 male and female mice (De et al, 2012; De Filippis et al, 2015). Nevertheless, the mechanism by which the absence of Mecp2 impairs modulation of Rho GTPases is currently unknown, highlighting our observations about the contribution of Mecp2 to p250GAP regulation in experience-dependent plasticity.…”

Section: Discussionmentioning

confidence: 99%

Mecp2 Mediates Experience-Dependent Transcriptional Upregulation of Ryanodine Receptor Type-3

Torres

Hidalgo

Kerr

2017

Front. Mol. Neurosci.

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Mecp2 is a DNA methylation reader that plays a critical role in experience-dependent plasticity. Increasing evidence supports a role for epigenetic modifications in activity-induced gene expression. Hence, candidate genes related to such phenomena are of great interest. Ryanodine receptors are intracellular calcium channels that contribute to hippocampal synaptic plasticity, dendritic spine remodeling, and participate in learning and memory processes. Here we exposed mice to the enriched environment (EE) paradigm, which through increased stimulation induces experience dependent-plasticity, to explore a role for methyl-cytosines, and Mecp2 in directing Ryanodine receptor 3 (Ryr3) transcriptional activity. EE induced a hippocampal-specific increase in the methylation of discrete cytosines located at a Ryr3 isoform promoter; chromatin immunoprecipitation experiments revealed that EE increased Mecp2 binding to this Ryr3 isoform promoter. Interestingly, the experimental paradigm induced robust Ryr3 upregulation, accompanied by miR132-dependent suppression of p250GAP, a pathway driving synaptogenesis. In contrast to WT mice, Mecp2-null mice showed diminished levels of Ryr3 and displayed impaired EE-induced Ryr3 upregulation, compromising miR132 dependent suppression of p250GAP and experience-dependent structural plasticity. Based on these results, we propose that Mecp2 acts as a transcriptional activator of Ryr3, contributing to experience-dependent plasticity.

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Section: Discussionmentioning

confidence: 99%

Mecp2 Mediates Experience-Dependent Transcriptional Upregulation of Ryanodine Receptor Type-3

Torres

Hidalgo

Kerr

2017

Front. Mol. Neurosci.

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“…Overexpression of BDNF appears to restore the dendritic defects in Mecp2 -null condition suggesting a molecular mechanism regulated by MECP2 to maintain the structural stability of neurons (Zhou et al, 2006; Larimore et al, 2009; Gao et al, 2015). Synaptic plasticity is also regulated by the expression or the phosphorylation of MECP2 (Collins et al, 2004; Dani et al, 2005; Asaka et al, 2006; Moretti et al, 2006; Chao et al, 2007; Zhang et al, 2008; Li et al, 2011; Noutel et al, 2011; Blackman et al, 2012; Na et al, 2012, 2013; Qiu et al, 2012; Zhong et al, 2012; Della Sala and Pizzorusso, 2014; Deng et al, 2014; De Filippis et al, 2015). Whether a similar mechanism to Rett or MECP2 duplication syndromes is altered in ASD individuals with MECP2 mutations needs to be further evaluated.…”

Section: Specific Syndromic Disorder Related Genesmentioning

confidence: 99%

A Subset of Autism-Associated Genes Regulate the Structural Stability of Neurons

Lin

Frei

Kilander

et al. 2016

Front. Cell. Neurosci.

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Autism spectrum disorder (ASD) comprises a range of neurological conditions that affect individuals’ ability to communicate and interact with others. People with ASD often exhibit marked qualitative difficulties in social interaction, communication, and behavior. Alterations in neurite arborization and dendritic spine morphology, including size, shape, and number, are hallmarks of almost all neurological conditions, including ASD. As experimental evidence emerges in recent years, it becomes clear that although there is broad heterogeneity of identified autism risk genes, many of them converge into similar cellular pathways, including those regulating neurite outgrowth, synapse formation and spine stability, and synaptic plasticity. These mechanisms together regulate the structural stability of neurons and are vulnerable targets in ASD. In this review, we discuss the current understanding of those autism risk genes that affect the structural connectivity of neurons. We sub-categorize them into (1) cytoskeletal regulators, e.g., motors and small RhoGTPase regulators; (2) adhesion molecules, e.g., cadherins, NCAM, and neurexin superfamily; (3) cell surface receptors, e.g., glutamatergic receptors and receptor tyrosine kinases; (4) signaling molecules, e.g., protein kinases and phosphatases; and (5) synaptic proteins, e.g., vesicle and scaffolding proteins. Although the roles of some of these genes in maintaining neuronal structural stability are well studied, how mutations contribute to the autism phenotype is still largely unknown. Investigating whether and how the neuronal structure and function are affected when these genes are mutated will provide insights toward developing effective interventions aimed at improving the lives of people with autism and their families.

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“…1,2 Conversely, the same CNF1-induced mechanisms that seem to trigger the harmful effects of these diseases (i.e., Rho GTPases activation, wide cellular actin reorganization and alteration of mitochondria homeostasis) have been exploited to relieve the symptoms of other severe neurological diseases. [14][15][16][17][18][19][20][21][22] As a result, there is a great attention for an inclusive study of this protein at the molecular level to decipher both its action as a toxin and as a potential drug. At this point, we think that the level of detail devoted to the structural characterization of the catalytic domain of the protein should be extended to the full-length CNF1.…”

Section: Discussionmentioning

confidence: 99%

“…The main effects of this process include the activation of a controlled immune response in the host and a wide reorganization of the actin cytoskeleton of the infected cell which is exploited for the bacterial uptake . CNF1 capability to directly affect Rho GTPases action and indirectly actin assembly and cellular bioenergetics has recently been exploited in the treatment of some severe neurological diseases, including Alzheimer's disease, Parkinson's disease and Rett syndrome …”

Section: Introductionmentioning

confidence: 99%

“…12,13 CNF1 capability to directly affect Rho GTPases action and indirectly actin assembly and cellular bioenergetics has recently been exploited in the treatment of some severe neurological diseases, including Alzheimer's disease, Parkinson's disease and Rett syndrome. [14][15][16][17][18][19][20][21][22] Several studies have pointed out the general structuration of CNF1 as an AB toxin, presenting two different receptorrecognition sites (an N-terminal 37LRP/67LR binding domain and a C-terminal Lu/BCAM binding domain) and a C-terminal catalytic domain catalyzing Rho deamidation. [23][24][25][26][27][28] The mechanism of internalization of this toxin is quite complex and requires its binding with both receptors, its transport via endocytosis and the release of the cleaved C-terminal domain in the cytosol after an acidic-dependent insertion of two hydrophobic regions in the endosomal membrane.…”

Section: Introductionmentioning

confidence: 99%

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High yield purification and first structural characterization of the full‐length bacterial toxin CNF1

Colarusso

Caterino

Fabbri

et al. 2017

Biotechnology Progress

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The Cytotoxic Necrotizing Factor 1 (CNF1) is a bacterial toxin secreted by certain Escherichia coli strains causing severe pathologies, making it a protein of pivotal interest in toxicology. In parallel, the CNF1 capability to influence important neuronal processes, like neuronal arborization, astrocytic support, and efficient ATP production, has been efficiently used in the treatment of neurological diseases, making it a promising candidate for therapy. Nonetheless, there are still some unsolved issues about the CNF1 mechanism of action and structuration probably caused by the difficulty to achieve sufficient amounts of the full-length protein for further studies. Here, we propose an efficient strategy for the production and purification of this toxin as a his-tagged recombinant protein from E. coli extracts (CNF1-H8). CNF1-H8 was expressed at the low temperature of 15°C to diminish its characteristic degradation. Then, its purification was achieved using an immobilized metal affinity chromatography (IMAC) and a size exclusion chromatography so as to collect up to 8 mg of protein per liter of culture in a highly pure form. Routine dynamic light scattering (DLS) experiments showed that the recombinant protein preparations were homogeneous and preserved this state for a long time. Furthermore, CNF1-H8 functionality was confirmed by testing its activity on purified RhoA and on HEp-2 cultured cells. Finally, a first structural characterization of the full-length toxin in terms of secondary structure and thermal stability was performed by circular dichroism (CD). These studies demonstrate that our system can be used to produce high quantities of pure recombinant protein for a detailed structural analysis. © 2017 American Institute of Chemical Engineers Biotechnol. Prog., 34:150-159, 2018.

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Modulation of Rho GTPases rescues brain mitochondrial dysfunction, cognitive deficits and aberrant synaptic plasticity in female mice modeling Rett syndrome

Cited by 42 publications

References 49 publications

Mecp2 Mediates Experience-Dependent Transcriptional Upregulation of Ryanodine Receptor Type-3

Mecp2 Mediates Experience-Dependent Transcriptional Upregulation of Ryanodine Receptor Type-3

A Subset of Autism-Associated Genes Regulate the Structural Stability of Neurons

High yield purification and first structural characterization of the full‐length bacterial toxin CNF1

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