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Schizophrenia likely results from poorly understood genetic and environmental factors. We studied the gene encoding the synaptic protein SHANK3 in 285 controls and 185 schizophrenia patients with unaffected parents. Two de novo mutations (R1117X and R536W) were identified in two families, one being found in three affected brothers, suggesting germline mosaicism. Zebrafish and rat hippocampal neuron assays revealed behavior and differentiation defects resulting from the R1117X mutant. As mutations in SHANK3 were previously reported in autism, the occurrence of SHANK3 mutations in subjects with a schizophrenia phenotype suggests a molecular genetic link between these two neurodevelopmental disorders.

Micro-RNAs (miRNAs) are short (∼21 nt) non-coding RNAs that regulate gene expression through the degradation or translational repression of mRNAs. Accumulating evidence points to a role of miRNA regulation in the pathogenesis of a wide range of neurodegenerative (ND) diseases such as, for example, Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis and Huntington disease (HD). Several systems level studies aimed to explore the role of miRNA regulation in NDs, but these studies remain challenging. Part of the problem may be related to the lack of sufficiently rich or homogeneous data, such as time series or cell-type-specific data obtained in model systems or human biosamples, to account for context dependency. Part of the problem may also be related to the methodological challenges associated with the accurate system-level modeling of miRNA and mRNA data. Here, we critically review the main families of machine learning methods used to analyze expression data, highlighting the added value of using shape-analysis concepts as a solution for precisely modeling highly dimensional miRNA and mRNA data such as the ones obtained in the study of the HD process, and elaborating on the potential of these concepts and methods for modeling complex omics data.

The Aryl hydrocarbon Receptor (AhR) is a xenobiotic sensor in vertebrates, regulating the metabolism of its own ligands. However, no ligand has been identified to date for any AhR in invertebrates. In C. elegans, the AhR ortholog, AHR-1, displays physiological functions. Therefore, we compared the transcriptomic and metabolic profiles of worms expressing AHR-1 or not and investigated the putative panel of chemical AHR-1 modulators. The metabolomic profiling indicated a role for AHR-1 in amino acids, carbohydrates, and fatty acids metabolism. The transcriptional profiling in neurons expressing AHR-1, identified 95 down-regulated genes and 76 up-regulated genes associated with neuronal and metabolic functions in the nervous system. A gene reporter system allowed us to identify several AHR-1 modulators including bacterial, dietary, or environmental compounds. These results shed new light on the biological functions of AHR-1 in C. elegans and perspectives on the evolution of the AhR functions across species.

There is no treatment for the neurodegenerative disorder Huntington disease (HD). Cystamine is a candidate drug; however, the mechanisms by which it operates remain unclear. We show here that cystamine increases levels of the heat shock DnaJ-containing protein 1b (HSJ1b) that are low in HD patients. HSJ1b inhibits polyQ-huntingtin-induced death of striatal neurons and neuronal dysfunction in Caenorhabditis elegans. This neuroprotective effect involves stimulation of the secretory pathway through formation of clathrin-coated vesicles containing brain-derived neurotrophic factor (BDNF). Cystamine increases BDNF secretion from the Golgi region that is blocked by reducing HSJ1b levels or by overexpressing transglutaminase. We demonstrate that cysteamine, the FDA-approved reduced form of cystamine, is neuroprotective in HD mice by increasing BDNF levels in brain. Finally, cysteamine increases serum levels of BDNF in mouse and primate models of HD. Therefore, cysteamine is a potential treatment for HD, and serum BDNF levels can be used as a biomarker for drug efficacy.

Background Several studies have suggested that vascular dysfunction plays an important role in Alzheimer’s disease. Aims We hypothesized that significant differences might be observed in the levels of blood endothelial biomarkers across elderly population of subjects with dementia. Methods We analyzed, in a prospective monocentric study, three different endothelial biomarkers, endothelial microparticles (EMPs), endothelial progenitor cells (EPCs) and circulating endothelial cells (CECs) in 132 older patients who underwent a full evaluation of a memory complaint. Results There was no difference in specific EMP, EPC or CEC levels between demented or non-demented patients, nor considering cognitive decline. Discussion Blood endothelial biomarkers may be too sensitive and it is likely that the multimorbidity observed in our patients may lead to opposite and confounding effects on endothelial biomarkers levels. Conclusion Unlike younger AD patients, our results suggest that endothelial biomarkers are not valuable for the diagnosis of dementia in elderly patients.

Huntington's disease (HD) is a neurodegenerative disease caused by polyglutamine expansion in the protein huntingtin (htt). Pathogenesis in HD appears to involve the formation of ubiquitinated neuronal intranuclear inclusions containing N-terminal mutated htt, abnormal protein interactions, and the aggregate sequestration of a variety of proteins (noticeably, transcription factors). To identify novel htt-interacting proteins in a simple model system, we used a yeast two-hybrid screen with a Caenorhabditis elegans activation domain library. We found a predicted WW domain protein (ZK1127.9) that interacts with N-terminal fragments of htt in two-hybrid tests. A human homologue of ZK1127.9 is CA150, a transcriptional coactivator with a N-terminal insertion that contains an imperfect (Gln-Ala)38tract encoded by a polymorphic repeat DNA. CA150 interacted in vitro with full-length htt from lymphoblastoid cells. The expression of CA150, measured immunohistochemically, was markedly increased in human HD brain tissue compared with normal age-matched human brain tissue, and CA150 showed aggregate formation with partial colocalization to ubiquitin-positive aggregates. In 432 HD patients, the CA150 repeat length explains a small, but statistically significant, amount of the variability in the onset age. Our data suggest that abnormal expression of CA150, mediated by interaction with polyglutamine-expanded htt, may alter transcription and have a role in HD pathogenesis.

We report that Sir2 activation through increased sir-2.1 dosage or treatment with the sirtuin activator resveratrol specifically rescued early neuronal dysfunction phenotypes induced by mutant polyglutamines in transgenic Caenorhabditis elegans . These effects are dependent on daf-16 (Forkhead). Additionally, resveratrol rescued mutant polyglutamine–specific cell death in neuronal cells derived from HdhQ111 knock-in mice. We conclude that Sir2 activation may protect against mutant polyglutamines.

Although the length of CAG repeat expansion may highly anticorrelates with the age at onset of Huntington disease (HD), genetic modifiers may have a significant impact in HD. One class of modifiers that has recently drawn attention is DNA repair genes. Although some DNA repair genes may be associated with somatic CAG expansion, the involvement of DNA repair genes might reach far beyond that phenomenon, notably in terms of stress response and compensation. HD is marked by neurodegeneration but also has an increasingly studied neurodevelopmental component. Recent advances in stem cells technologies now allow for a comprehensive study of neurodevelopmental processes in vitro, enabling to investigate the role of stress response mechanisms such as DNA repair in the earliest phases of the HD process and test whether DNA damage and repair features established at the time of neuronal differentiation might be conserved in adult neurons.To this end, we study DNA damage and DNA Damage Response (DDR) in human HD stem cells including an isogenic pair of patient-derived Neural Stem Cells (NSCs) and its genetically corrected counterpart differentiated in vitro from induced Pluripotent Stem Cells (iPSCs). To this end, we use markers of DNA damage levels and reporters of DDR pathway activities in response to Single Strand Breaks (SSB) and Double Strand Breaks (DSB).We will present results on the alteration of SSB and DSB responses in human HD NSCs, discussing how understanding the specificities of DDR alterations during neuronal differentiation may shed light on disease mechanisms, seminal effects and potential therapeutic targets.

Huntington's disease (HD) is a neurodegenerative disease caused by polyglutamine (polyQ) expansion in the protein huntingtin (htt). Pathogenesis in HD seems to involve the formation of neuronal intranuclear inclusions and the abnormal regulation of transcription and signal transduction. To identify previously uncharacterized htt-interacting proteins in a simple model system, we used a yeast two-hybrid screen with a Caenorhabditis elegans activation domain library. We found a predicted SH3 domain protein (K08E3.3b) that interacts with N-terminal htt in two-hybrid tests. A human homolog of K08E3.3b is the Cdc42-interacting protein 4 (CIP4), a protein involved in Cdc42 and Wiskott-Aldrich syndrome protein-dependent signal transduction. CIP4 interacted in vitro with full-length htt from lymphoblastoid cells. Neuronal CIP4 immunoreactivity increased with neuropathological severity in the neostriatum of HD patients and partially colocalized to ubiquitin-positive aggregates. Marked CIP4 overexpression also was observed in Western blot from human HD brain striatum. The overexpression of CIP4 induced the death of striatal neurons. Our data suggest that CIP4 accumulation and cellular toxicity may have a role in HD pathogenesis.

Sirtuin activity revisited Overexpression of sirtuins has been reported to increase lifespan in Caenorhabditis elegans and Drosophila melanogaster . The effects of dietary restriction on the lifespan of flies have also been reported to be Sir2-dependent. Here it is shown that these findings are attributable to the confounding effects of genetic background. This work suggests that the life-extending effect of sirtuin overexpression may be limited to yeast, and also supports studies in yeast and C. elegans that show that the effects of dietary restriction are not mediated by sirtuins. Overexpression of sirtuins (NAD + -dependent protein deacetylases) has been reported to increase lifespan in budding yeast ( Saccharomyces cerevisiae ), Caenorhabditis elegans and Drosophila melanogaster 1 , 2 , 3 . Studies of the effects of genes on ageing are vulnerable to confounding effects of genetic background 4 . Here we re-examined the reported effects of sirtuin overexpression on ageing and found that standardization of genetic background and the use of appropriate controls abolished the apparent effects in both C. elegans and Drosophila . In C. elegans , outcrossing of a line with high-level sir-2.1 overexpression 1 abrogated the longevity increase, but did not abrogate sir-2.1 overexpression. Instead, longevity co-segregated with a second-site mutation affecting sensory neurons. Outcrossing of a line with low-copy-number sir-2.1 overexpression 2 also abrogated longevity. A Drosophila strain with ubiquitous overexpression of dSir2 using the UAS-GAL4 system was long-lived relative to wild-type controls, as previously reported 3 , but was not long-lived relative to the appropriate transgenic controls, and nor was a new line with stronger overexpression of dSir2 . These findings underscore the importance of controlling for genetic background and for the mutagenic effects of transgene insertions in studies of genetic effects on lifespan. The life-extending effect of dietary restriction on ageing in Drosophila has also been reported to be dSir2 dependent 3 . We found that dietary restriction increased fly lifespan independently of dSir2 . Our findings do not rule out a role for sirtuins in determination of metazoan lifespan, but they do cast doubt on the robustness of the previously reported effects of sirtuins on lifespan in C. elegans and Drosophila .