Landscape of ribosome-engaged transcript isoforms reveals extensive neuronal-cell-class-specific alternative splicing programs

Nervous system function relies on complex assemblies of distinct neuronal cell types that have unique anatomical and functional properties instructed by molecular programs. Alternative splicing is a key mechanism for the expansion of molecular repertoires, and protein splice isoforms shape neuronal cell surface recognition and function. However, the logic of how alternative splicing programs are arrayed across neuronal cells types is poorly understood. We systematically mapped ribosome-associated transcript isoforms in genetically defined neuron types of the mouse forebrain. Our dataset provides an extensive resource of transcript diversity across major neuron classes. We find that neuronal transcript isoform profiles reliably distinguish even closely related classes of pyramidal cells and inhibitory interneurons in the mouse hippocampus and neocortex. These highly specific alternative splicing programs selectively control synaptic proteins and intrinsic neuronal properties. Thus, transcript diversification via alternative splicing is a central mechanism for the functional specification of neuronal cell types and circuits

Regional and subtype-dependent miRNA signatures in sporadic Creutzfeldt-Jakob disease are accompanied by alterations in miRNA silencing machinery and biogenesis

Increasing evidence indicates that microRNAs (miRNAs) are contributing factors to neurodegeneration. Alterations in miRNA signatures have been reported in several neurodegenerative dementias, but data in prion diseases are restricted to ex vivo and animal models. The present study identified significant miRNA expression pattern alterations in the frontal cortex and cerebellum of sporadic Creutzfeldt-Jakob disease (sCJD) patients. These changes display a highly regional and disease subtype-dependent regulation that correlates with brain pathology. We demonstrate that selected miRNAs are enriched in sCJD isolated Argonaute(Ago)-binding complexes in disease, indicating their incorporation into RNA-induced silencing complexes, and further suggesting their contribution to disease-associated gene expression changes. Alterations in the miRNA-mRNA regulatory machinery and perturbed levels of miRNA biogenesis key components in sCJD brain samples reported here further implicate miRNAs in sCJD gene expression (de)regulation. We also show that a subset of sCJD-altered miRNAs are commonly changed in Alzheimer's disease, dementia with Lewy bodies and fatal familial insomnia, suggesting potential common mechanisms underlying these neurodegenerative processes. Additionally, we report no correlation between brain and cerebrospinal fluid (CSF) miRNA-profiles in sCJD, indicating that CSF-miRNA profiles do not faithfully mirror miRNA alterations detected in brain tissue of human prion diseases. Finally, utilizing a sCJD MM1 mouse model, we analyzed the miRNA deregulation patterns observed in sCJD in a temporal manner. While fourteen sCJD-related miRNAs were validated at clinical stages, only two of those were changed at early symptomatic phase, suggesting that the miRNAs altered in sCJD may contribute to later pathogenic processes. Altogether, the present work identifies alterations in the miRNA network, biogenesis and miRNA-mRNA silencing machinery in sCJD, whereby contributions to disease mechanisms deserve further investigation.This work was supported by the Robert Koch Institute through funds from the Federal Ministry of Health (grant no. 1369-341) to IZ, by the Seventh Framework Program of the European Commission (Grant No. 278486 [DEVELAGE project]), by the Spanish Ministry of Health, Instituto Carlos III (Fondo de Investigación Sanitaria [FIS] PI1100968, FIS PI14/00757 and by CIBERNED (Network center for biomedical research of neurodegenerative diseases) project BESAD-P to IF, by the Spanish Ministry of Health, Instituto Carlos III-Fondo Social Europeo (CP16/00041) to FL, by the Red Nacional de priones (AGL2015-71764-REDT- MINECO) to JADR, FL, IZ, JMT and IF, by the bilateral IKYDA project (ID 57260006) to FL, IZ and TS, by the Spanish Ministry of Economy and Competitiveness (BFU2016-80039-R) (AEI/MINEICO/FEDER, UE) and the “Maria de Maeztu” Program for Units of Excellence in R&D (MDM-2014-0370) to JD, by the Spanish Ministry of Economy and Competitiveness (SAF2014-60551-R) to EM and by the Spanish Ministry of Economy, Industry and Competitiveness (MEICO) (BFU2015-67777-R), the Generalitat de Catalunya (SGR2014-1218), CIBERNED (PRY-2016-2, MFDEND), La Caixa Obra Social Foundation and La Marató de TV3 to JADR

Alternative splicing: a pivotal step between eukaryotic transcription and translation

Alternative splicing was discovered simultaneously with splicing over three decades ago. Since then, an enormous body of evidence has demonstrated the prevalence of alternative splicing in multicellular eukaryotes, its key roles in determining tissue- and species-specific differentiation patterns, the multiple post- and co-transcriptional regulatory mechanisms that control it, and its causal role in hereditary disease and cancer. The emerging evidence places alternative splicing in a central position in the flow of eukaryotic genetic information, between transcription and translation, in that it can respond not only to various signalling pathways that target the splicing machinery but also to transcription factors and chromatin structure.Fil: Kornblihtt, Alberto Rodolfo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; ArgentinaFil: Schor, Ignacio Esteban. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; ArgentinaFil: Alló, Mariano. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; ArgentinaFil: Dujardin, Gwendal. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; ArgentinaFil: Petrillo, Ezequiel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; ArgentinaFil: Muñoz, Manuel Javier. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; Argentin

Int J Behav Med

Background Due to their impact on premature mortality and long-term disabilities, a better understanding of health risk behavior (HRB) determinants among college students is crucial in order to build the most appropriate prevention tools. Although self-esteem appears to be a relevant candidate, a clear picture summarizing its multiple links with HRB is lacking to guide clinicians and researchers. This study aims to provide a systematic review of the associations between health risk behavior and self-esteem among college students. Methods This search was performed in several databases on 02/02/17. Study eligibility criteria were original articles in peer-reviewed journals, in English; observational quantitative studies; among college students; and investigated the association between self-esteem and HRB. The PRISMA statements were complied with. Results One hundred fifteen articles were included: 46 on substance use, 35 on sexual behavior, 11 on nutritional habits, 27 on physical activity, and 5 on other HRB. Most studies reported an association between higher self-esteem and healthier behavior. For alcohol consumption and number of sexual partners, both negative and positive associations have been reported. Directionality was investigated in a few studies suggesting potential bidirectional effects. Conclusions This review points out the need for consensus for the definition of self-esteem and HRB. There was high heterogeneity in (1) the measurement of self-esteem either in the concept measured (global vs. domain) or in the way to implement validated tools; and (2) the definition of HRB. Self-esteem seems to be a relevant target to intervene on HRB, especially alcohol abuse and physical activity