Distinct Transcriptome Expression of the Temporal Cortex of the Primate Microcebus murinus during Brain Aging versus Alzheimer's Disease-Like Pathology

Aging is the primary risk factor of neurodegenerative disorders such as Alzheimer's disease (AD). However, the molecular events occurring during brain aging are extremely complex and still largely unknown. For a better understanding of these age-associated modifications, animal models as close as possible to humans are needed. We thus analyzed the transcriptome of the temporal cortex of the primate Microcebus murinus using human oligonucleotide microarrays (Affymetrix). Gene expression profiles were assessed in the temporal cortex of 6 young adults, 10 healthy old animals and 2 old, “AD-like” animals that presented ß-amyloid plaques and cortical atrophy, which are pathognomonic signs of AD in humans. Gene expression data of the 14,911 genes that were detected in at least 3 samples were analyzed. By SAM (significance analysis of microarrays), we identified 47 genes that discriminated young from healthy old and “AD-like” animals. These findings were confirmed by principal component analysis (PCA). ANOVA of the expression data from the three groups identified 695 genes (including the 47 genes previously identified by SAM and PCA) with significant changes of expression in old and “AD-like” in comparison to young animals. About one third of these genes showed similar changes of expression in healthy aging and in “AD-like” animals, whereas more than two thirds showed opposite changes in these two groups in comparison to young animals. Hierarchical clustering analysis of the 695 markers indicated that each group had distinct expression profiles which characterized each group, especially the “AD-like” group. Functional categorization showed that most of the genes that were up-regulated in healthy old animals and down-regulated in “AD-like” animals belonged to metabolic pathways, particularly protein synthesis. These data suggest the existence of compensatory mechanisms during physiological brain aging that disappear in “AD-like” animals. These results open the way to new exploration of physiological and “AD-like” aging in primates

A New Isoform of the Histone Demethylase JMJD2A/KDM4A Is Required for Skeletal Muscle Differentiation

In proliferating myoblasts, muscle specific genes are silenced by epigenetic modifications at their promoters, including histone H3K9 methylation. Derepression of the promoter of the gene encoding the myogenic factor myogenin (Myog) is key for initiation of muscle differentiation. The mechanism of H3K9 demethylation at the Myog promoter is unclear, however. Here, we identify an isoform of the histone demethylase JMJD2A/KDM4A that lacks the N-terminal demethylase domain (ΔN-JMJD2A). The amount of ΔN-JMJD2A increases during differentiation of C2C12 myoblasts into myotubes. Genome-wide expression profiling and exon-specific siRNA knockdown indicate that, in contrast to the full-length protein, ΔN-JMJD2A is necessary for myotube formation and muscle-specific gene expression. Moreover, ΔN-JMJD2A promotes MyoD-induced conversion of NIH3T3 cells into muscle cells. ChIP-on-chip analysis indicates that ΔN-JMJD2A binds to genes mainly involved in transcriptional control and that this binding is linked to gene activation. ΔN-JMJD2A is recruited to the Myog promoter at the onset of differentiation. This binding is essential to promote the demethylation of H3K9me2 and H3K9me3. We conclude that induction of the ΔN-JMJD2A isoform is crucial for muscle differentiation: by directing the removal of repressive chromatin marks at the Myog promoter, it promotes transcriptional activation of the Myog gene and thus contributes to initiation of muscle-specific gene expression

C3-symmetric peptide scaffolds are functional mimetics of trimeric CD40L.

Interaction between CD40, a member of the tumor necrosis factor receptor (TNFR) superfamily, and its ligand CD40L, a 39-kDa glycoprotein, is essential for the development of humoral and cellular immune responses. Selective blockade or activation of this pathway provides the ground for the development of new treatments against immunologically based diseases and malignancies. Like other members of the TNF superfamily, CD40L monomers self-assemble around a threefold symmetry axis to form noncovalent homotrimers that can each bind three receptor molecules. Here, we report on the structure-based design of small synthetic molecules with C3 symmetry that can mimic CD40L homotrimers. These molecules interact with CD40, compete with the binding of CD40L to CD40, and reproduce, to a certain extent, the functional properties of the much larger homotrimeric soluble CD40L. Architectures based on rigid C3-symmetric cores may thus represent a general approach to mimicking homotrimers of the TNF superfamily

Mechanisms of human cerebellar dysmetria: experimental evidence and current conceptual bases.

The human cerebellum contains more neurons than any other region in the brain and is a major actor in motor control. Cerebellar circuitry is unique by its stereotyped architecture and its modular organization. Understanding the motor codes underlying the organization of limb movement and the rules of signal processing applied by the cerebellar circuits remains a major challenge for the forthcoming decades. One of the cardinal deficits observed in cerebellar patients is dysmetria, designating the inability to perform accurate movements. Patients overshoot (hypermetria) or undershoot (hypometria) the aimed target during voluntary goal-directed tasks. The mechanisms of cerebellar dysmetria are reviewed, with an emphasis on the roles of cerebellar pathways in controlling fundamental aspects of movement control such as anticipation, timing of motor commands, sensorimotor synchronization, maintenance of sensorimotor associations and tuning of the magnitudes of muscle activities. An overview of recent advances in our understanding of the contribution of cerebellar circuitry in the elaboration and shaping of motor commands is provided, with a discussion on the relevant anatomy, the results of the neurophysiological studies, and the computational models which have been proposed to approach cerebellar function.Journal ArticleResearch Support, Non-U.S. Gov'tReviewSCOPUS: ar.jinfo:eu-repo/semantics/publishe

The endocannabinoid system in guarding against fear, anxiety and stress

The endocannabinoid (eCB) system has emerged as a central integrator linking the perception of external and internal stimuli to distinct neurophysiological and behavioural outcomes (such as fear reaction, anxiety and stress-coping), thus allowing an organism to adapt to its changing environment. eCB signalling seems to determine the value of fear-evoking stimuli and to tune appropriate behavioural responses, which are essential for the organism's long-term viability, homeostasis and stress resilience; and dysregulation of eCB signalling can lead to psychiatric disorders. An understanding of the underlying neural cell populations and cellular processes enables the development of therapeutic strategies to mitigate behavioural maladaptation.B.L. was supported by the German Research Foundation (SFB TRR 58, CRC 1080 and FOR 926); G.M. by the Institut national de la santé et de la recherche médicale (INSERM), the European Commission Seventh Framework Programme (REPROBESITY, HEALTH-F2-2008-223713, PAINCAGE and HEALTH-2014-603191), the European Research Council (Endofood, ERC-2010-StG−260515, CannaPreg and ERC-2014-PoC-640923), the Fondation pour la Recherche Medicale (DRM20101220445), the Human Frontiers Science Program, Region Aquitaine, Agence Nationale de la Recherche (ANR Blanc NeuroNutriSens ANR-13-BSV4-0006 and BRAIN ANR-10-LABX-0043); R.M. by the grants SAF2014-59648P, RETICS-RTA#RD12/0028/0023, AGAUR#2014-SGR-1547 and Health-F2-2013-602891; and C.J.H. by the US National Institutes of Health grants DA038663, DA026996 and MH102838