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Physiology: movement organs, voice and skin --- Adhesion cellulaire --- Biochemie --- Biochimie --- Celadhesie --- Cell adhesion --- Fysiologie --- Physiologie --- Academic collection --- Theses --- Fibronectins --- Biosynthesis

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The discovery of microRNAs has revealed an unexpected and spectacular additional level of fine tuning of the genome and how genes are used again and again in different combinations to generate the complexity that underlies for instance the brain. Since the initial studies performed in C.elegans, we have gone a far way to begin to understand how microRNA pathways can have an impact on health and disease in human. Although microRNAs are abundantly expressed in the brain, relatively little is known about the multiple functions of these RNA molecules in the nervous system. Nevertheless, we know already that microRNA pathways play major roles in the proliferation, differentiation, function and maintenance of neuronal cells. Several intriguing studies have linked microRNAs as major regulators of the neuronal phenotype, and have implicated specific microRNAs in the regulation of synapse formation and plasticity. Dysfunction of microRNA pathways is also slowly emerging as a potential important contributor to the pathogenesis of major neurodegenerative disorders such as Alzheimer’s disease and Parkinson’s disease. These novel insights appear to be particular promising for the understanding of the very frequent and badly understood sporadic forms of these diseases as compared to the genetic forms. Thus, the better understanding of the implications of this novel field of molecular biology is crucial for the broad area of neurosciences, from the fundamental aspects to the clinic, and from novel diagnostic to potentially therapeutic applications for severe neurological and maybe psychiatric diseases.

Genetics --- Molecular biology --- Neuropathology --- neurologie --- genexpressie

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The discovery of microRNAs has revealed an unexpected and spectacular additional level of fine tuning of the genome and how genes are used again and again in different combinations to generate the complexity that underlies for instance the brain. Since the initial studies performed in C.elegans, we have gone a far way to begin to understand how microRNA pathways can have an impact on health and disease in human. Although microRNAs are abundantly expressed in the brain, relatively little is known about the multiple functions of these RNA molecules in the nervous system. Nevertheless, we know already that microRNA pathways play major roles in the proliferation, differentiation, function and maintenance of neuronal cells. Several intriguing studies have linked microRNAs as major regulators of the neuronal phenotype, and have implicated specific microRNAs in the regulation of synapse formation and plasticity. Dysfunction of microRNA pathways is also slowly emerging as a potential important contributor to the pathogenesis of major neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease. These novel insights appear to be particular promising for the understanding of the very frequent and badly understood sporadic forms of these diseases as compared to the genetic forms. Thus, the better understanding of the implications of this novel field of molecular biology is crucial for the broad area of neurosciences, from the fundamental aspects to the clinic, and from novel diagnostic to potentially therapeutic applications for severe neurological and maybe psychiatric diseases.

Biomedicine. --- Neurosciences. --- Gene Expression. --- Medicine. --- Gene expression. --- Médecine --- Expression génique --- Neurosciences --- Academic collection --- MicroRNAs --- Synaptic Transmission --- Neurodegenerative Diseases --- Genetic Therapy. --- DNA Therapy --- Gene Therapy, Somatic --- Genetic Therapy, Gametic --- Genetic Therapy, Somatic --- Therapy, DNA --- Therapy, Gene --- Therapy, Somatic Gene --- Gene Therapy --- Somatic Gene Therapy --- Gametic Genetic Therapies --- Gametic Genetic Therapy --- Genetic Therapies --- Genetic Therapies, Gametic --- Genetic Therapies, Somatic --- Somatic Genetic Therapies --- Somatic Genetic Therapy --- Therapies, Gametic Genetic --- Therapies, Genetic --- Therapies, Somatic Genetic --- Therapy, Gametic Genetic --- Therapy, Genetic --- Therapy, Somatic Genetic --- Gene Transfer Techniques --- Genetic Services --- Genes, Transgenic, Suicide --- genetics. --- Academic collection - Academische collectie - Collection academique --- Genetic regulation --- Molecular neurobiology --- Neural transmission --- Small interfering RNA --- Genetic Therapy --- piRNA (Piwi-interacting RNA) --- Piwi-interacting RNA --- Piwi protein-interacting RNA --- rasiRNA (Repeat-associated small interfering RNA) --- Repeat-associated siRNA --- Repeat-associated small interfering RNA --- Scan RNA --- scnRNA (Small scan RNA) --- Short hairpin RNA --- Short interfering RNA --- shRNA (Short hairpin RNA) --- siRNA (Small interfering RNA) --- Small hairpin RNA --- Small scan RNA --- tasiRNA (Trans-acting small interfering RNA) --- Trans-acting siRNA --- Trans-acting small interfering RNA --- Antisense RNA --- Nerve transmission --- Nervous transmission --- Neurotransmission --- Synaptic transmission --- Transmission of nerve impulses --- Neural circuitry --- Neurophysiology --- Neurotransmitters --- Molecular neurology --- Nervous system --- Molecular biology --- Neurobiology --- Gene expression --- Gene expression regulation --- Gene regulation --- Biosynthesis --- Cellular control mechanisms --- Molecular genetics --- Disorders&delete& --- Gene therapy --- Genetic aspects --- genetics --- Molecular aspects --- Regulation --- Disorders

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Schizophrenia is a major psychiatric illness that occurs in approximately 0.5% of all individuals. This disease is characterized by the presence of different classes of symptoms. Firstly, there are positive symptoms such as delusions and hallucinations. Secondly, there are negative symptoms such as social isolation, blunted emotions, poverty of speech and anhedonia – the inability to experience pleasure from normally pleasurable life events. Lastly, there are impairments in various cognitive domains affecting short-term planning and working memory.Different genes that play an important role in brain development and functioning have been implied in schizophrenia. The presence of these faulty gene variants gives rise to subtle dysfunctions in multiple brain circuits. Firstly, there is a hyperactivity of the mesolimbic tract that connects the brain stem with the striatum and uses the neurotransmitter dopamine. This hyperactivity is held responsible for the positive symptoms. Secondly, there is a dysregulation of internal circuits in the cerebral cortex and the hippocampus that use the neurotransmitters glutamate and GABA. The malfunctioning of these circuits is assumed to be directly responsible for the negative and the cognitive symptoms. The existing drugs against schizophrenia – the antipsychotics – work primarily by blocking the activity of the mesolimbic tract. Therefore, they are only effective in alleviating the positive symptoms. A better understanding of the mechanisms leading to schizophrenia is a prerequisite for the rational development of more effective medication. One of the crucial steps in the fundamental research of diseases is the development of animal models. For psychiatric diseases, this is a daunting task since it is hard to model the typically human symptoms of those diseases in animals Yet, in the case of schizophrenia, a number of behavioural tests exist that can diagnose abnormalities in animals that mimic the different classes of schizophrenia symptoms. If these behavioural abnormalities are present, those animal models can be used to study in detail the brain circuits that have been implied in schizophrenia.In the broader framework of our research into the function of g-Secretase, a protein complex that cleaves other proteins and in that way regulates their function, we created a knockout mouse that lacks a specific variant of this complex, the Aph1B/C-g-Secretase (Aph1BC-/- mice). These mice perform poorly on the specific behavioural tests that are used to model the positive and cognitive symptoms of schizophrenia. Furthermore, the administration of antipsychotics can correct the impairment in one of the assays that measures the positive symptoms There are also different lines of evidence for abnormalities in the two major brain circuits implied in schizophrenia. Interestingly, the Aph1B/C variant of the g-Secretase complex is present in high levels in the circuit where the primary deficit in schizophrenia is thought to be.Neuregulin-1 (Nrg1) is one of the proteins that are cleaved by g-Secretase. The gene that encodes this protein has convincingly been linked to an increased risk of schizophrenia. Here, it is shown that the cleavage of Nrg1 is disturbed in the brain of the Aph1BC-/- mice. Further, one of the Nrg1 variants that increase the risk of schizophrenia is less susceptible to cleavage by Aph1B/C-g-Secretase than wild-type Nrg1. In light of these results, it is worthwhile to further investigate the potential of g-Secretase stimulation as a therapeutic strategy against schizophrenia and related neuropsychiatric diseases. To validate this strategy, it should first be established that phenotypes we have observed in Aph1BC-/- mice are acute, and not developmental, in nature. Subsequently, one could think about the development of small molecule drugs that increase g-Secretase expression or activi