Dystrophins, Utrophins, and Associated Scaffolding Complexes: Role in Mammalian Brain and Implications for Therapeutic Strategies

Perronnet, Caroline; Vaillend, Cyrille

doi:10.1155/2010/849426

Cited by 61 publications

(94 citation statements)

References 203 publications

(258 reference statements)

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“…The DGC is a transmembrane signaling complex present in striate and cardiac muscle cells, kidney tubular epithelial cells, neurons, and astrocytes, linking the extracellular matrix to the actin cytoskeleton (reviewed in [82][83][84]). The DGC is essential for normal brain development and synaptic function and for maintaining the structural integrity of the sarcolemma.…”

Section: The Dystrophin-glycoprotein Complexmentioning

confidence: 99%

“…Mutations affecting the formation, post-translational modification, or function of the DGC cause multiple forms of hereditary muscle dystrophies. While the contribution of the DGC to muscle disease has been thoroughly investigated, patients with Duchenne and Becker muscular dystrophies also show signs of cognitive impairments and learning disabilities that have been related to its functions in the CNS [85,83]. In neurons, dystrophin was shown initially to be present in PSD fraction of purified brain membranes [86].…”

Section: The Dystrophin-glycoprotein Complexmentioning

confidence: 99%

“…In neurons, dystrophin was shown initially to be present in PSD fraction of purified brain membranes [86]. Subsequent studies demonstrated its association with a subset of GABAergic synapses [87,88], where it regulates GABA A R clustering and GABAergic synaptic function, as well as glutamatergic synaptic plasticity (reviewed in [83,82]). In mdx mice, direct involvement of dystrophin in synaptic alterations has been demonstrated by dystrophin rescue experiments, which normalize mIPSC amplitude and frequency, as well as LTP in CA1 pyramidal cells [89,90].…”

Section: The Dystrophin-glycoprotein Complexmentioning

confidence: 99%

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Molecular and functional heterogeneity of GABAergic synapses

Fritschy

Panzanelli

Tyagarajan

2012

Cell. Mol. Life Sci.

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Knowledge of the functional organization of the GABAergic system, the main inhibitory neurotransmitter system, in the CNS has increased remarkably in recent years. In particular, substantial progress has been made in elucidating the molecular mechanisms underlying the formation and plasticity of GABAergic synapses. Evidence available ascribes a key role to the cytoplasmic protein gephyrin to form a postsynaptic scaffold anchoring GABA(A) receptors along with other transmembrane proteins and signaling molecules in the postsynaptic density. However, the mechanisms of gephyrin scaffolding remain elusive, notably because gephyrin can auto-aggregate spontaneously and lacks PDZ protein interaction domains found in a majority of scaffolding proteins. In addition, the structural diversity of GABA(A) receptors, which are pentameric channels encoded by a large family of subunits, has been largely overlooked in these studies. Finally, the role of the dystrophin-glycoprotein complex, present in a subset of GABAergic synapses in cortical structures, remains ill-defined. In this review, we discuss recent results derived mainly from the analysis of mutant mice lacking a specific GABA(A) receptor subtype or a core protein of the GABAergic postsynaptic density (neuroligin-2, collybistin), highlighting the molecular diversity of GABAergic synapses and its relevance for brain plasticity and function. In addition, we discuss the contribution of the dystrophin-glycoprotein complex to the molecular and functional heterogeneity of GABAergic synapses. AbstractKnowledge of the functional organization of the GABAergic system, the main inhibitory neurotransmitter system, in the CNS has increased remarkably in recent years. In particular, substantial progress has been made in elucidating the molecular mechanisms underlying formation and plasticity of GABAergic synapses. Evidence available ascribes a key role to the cytoplasmic protein gephyrin to form a postsynaptic scaffold anchoring GABA A receptors along with other transmembrane proteins and signaling molecules in the postsynaptic density. However, the mechanisms of gephyrin scaffolding remain elusive, notably because gephyrin can auto-aggregate spontaneously and lacks PDZ protein interaction domains found in a majority of scaffolding proteins. In addition, the structural diversity of GABA A receptors, which are pentameric channels encoded by a large family of subunits, has been largely overlooked in these studies. Finally, the role of the dystrophin-glycoprotein complex, present in a subset of GABAergic synapses in cortical structures, remains ill-defined. In this review, we discuss recent results derived mainly from the analysis of mutant mice lacking a specific GABA A receptor subtype or a core protein of the GABAergic postsynaptic density (neuroligin-2, collybistin), highlighting the molecular diversity of GABAergic synapses and its relevance for brain plasticity and function. In addition, we discuss the contribution of the dystrophinglycoprotein complex to the molecular ...

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Section: The Dystrophin-glycoprotein Complexmentioning

confidence: 99%

Section: The Dystrophin-glycoprotein Complexmentioning

confidence: 99%

Section: The Dystrophin-glycoprotein Complexmentioning

confidence: 99%

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Molecular and functional heterogeneity of GABAergic synapses

Fritschy

Panzanelli

Tyagarajan

2012

Cell. Mol. Life Sci.

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“…[7][8][9][10][11][12] Moreover, a higher incidence of different neuropsychiatric disorders, such as autism spectrum, attention deficit hyperactivity disorder, obsessive-compulsive disorders and social behavior problems has been revealed among affected males. [13][14][15][16][17] The impact of DMD on cognitive ability in cognitively healthy populations has not been studied to the best of our knowledge; therefore, in the current study we aim to investigate whether singlenucleotide DMD variants associate with variability in cognitive functions in general populations, suggesting loci in the DMD contributing to cognition, besides genuine DMD variants.…”

Section: Introductionmentioning

confidence: 99%

The dystrophin gene and cognitive function in the general population

et al. 2014

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The aim of our study is to investigate whether single-nucleotide dystrophin gene (DMD) variants associate with variability in cognitive functions in healthy populations. The study included 1240 participants from the Erasmus Rucphen family (ERF) study and 1464 individuals from the Rotterdam Study (RS). The participants whose exomes were sequenced and who were assessed for various cognitive traits were included in the analysis. To determine the association between DMD variants and cognitive ability, linear (mixed) modeling with adjustment for age, sex and education was used. Moreover, Sequence Kernel Association Test (SKAT) was used to test the overall association of the rare genetic variants present in the DMD with cognitive traits. Although no DMD variant surpassed the prespecified significance threshold (Po1 × 10 − 4 ), rs147546024:A4G showed strong association (β = 1.786, P-value = 2.56 × 10 − 4 ) with block-design test in the ERF study, while another variant rs1800273:G4A showed suggestive association (β = − 0.465, P-value = 0.002) with Mini-Mental State Examination test in the RS. Both variants are highly conserved, although rs147546024:A4G is an intronic variant, whereas rs1800273:G4A is a missense variant in the DMD which has a predicted damaging effect on the protein. Further gene-based analysis of DMD revealed suggestive association (P-values = 0.087 and 0.074) with general cognitive ability in both cohorts. In conclusion, both single variant and gene-based analyses suggest the existence of variants in the DMD which may affect cognitive functioning in the general populations.

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“…De façon remarquable, les tcDNA sont également capables d'induire un saut d'exon efficace dans le coeur des souris traitées, conduisant à une amélioration de la fonction cardiaque mesurée par la fraction de raccourcissement 1 , ce qui représente un avantage majeur comparé aux AON actuellement utilisés en clinique ( Figure 2C). Dans ce travail, nous avons aussi mis en évidence une correction des réponses émotionnelles naturellement exacerbées, qui peuvent être liées à des difficultés d'apprentissage, voire parfois des défauts cognitifs chez les sujets dystrophiques ( Figure 2D) [9]. Cette partie de l'étude, menée en collaboration avec une équipe de l'Institut des neurosciences Paris Saclay (CNRS/Université Paris-Sud), démontre que la forme Dp427 de la dystrophine est cruciale pour le bon fonctionnement de certains neurones, et que les problèmes comportementaux observés lorsqu'il y a un déficit de cette protéine sont au moins partiellement réversibles chez la souris dystrophique adulte.…”

Section: Nouvelleunclassified