Searching for somatic de novo mutations in Semantic Dementia
Projectomschrijving
Semantische dementie (SD) is een subtype van frontotemporale dementie en wordt gekenmerkt door ernstige taalstoornissen, waarbij het begrip van gesproken of geschreven taal geheel verloren gaat. Dit wordt veroorzaakt door een verval van zenuwcellen dat zich beperkt tot het voorste deel van de slaap- of temporaalkwab. Dit doet vermoeden dat er plaatselijke veranderingen in het DNA optreden.
Doel
De onderzoekers hopen met behulp van innovatieve methoden, waaronder het zogeheten ‘deep sequencen’ van DNA uit de hersenen van mensen met SD om genetische afwijkingen op te sporen, meer te weten te komen over het ziekteproces van SD. Dit kan het startpunt zijn voor de ontwikkeling van medicijnen die SD kunnen vertragen of stoppen.
Aanpak
De onderzoekers richten zich in dit project op mogelijke somatische de novo mutaties (DNM), oftewel genetische fouten in de hersenen die mogelijk de oorzaak zijn van SD. Bij een aantal hersenziekten, zoals autisme en schizofrenie, zijn deze fouten al vastgesteld.
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Samenvatting van de aanvraag
Semantic dementia (SD) is a clinically and pathologically well-defined brain disease with complete loss of language comprehension, occurring around 60 years. It leads to a complete social isolation of the patient and death within 8 -15 years. Severe and asymmetric atrophy of the anterior temporal cortex is the characteristic feature on MRI. Severe neuron loss, dystrophic neurites and round neuronal inclusions in the temporal cortex and dentate gyrus of the hippocampus are the neuropathological hallmarks. The cause of the disease is completely unknown, and any effective treatment is lacking. Genetic factors probably play an important role, although SD never occurs in families. Our hypothesis is that the pathophysiology of the disease process can be elucidated by investigating the presence somatic de novo mutations (DNMs), RNA expression patterns and proteomics strictly in the affected brain regions: temporal cortex and dentate gyrus of the hippocampus. Here we propose a unique (epi-)genetic-proteomic approach to come to the mechanistic understanding of the disease process and to detect somatic DNM in a subset of neurons of the temporal cortex (and the granular layer of the dentate gyrus) of SD brains, through: A. exploring all genetic and molecular mechanisms at the ultimate topographic level: 1. We will dissect genetic abnormalities of the temporal cortex and dentate gyrus, as most involved brain regions, at the level of somatic de novo mutations (DNM), as well as at the single-cell RNA expression level of the granular cells of the dentate gyrus. 2. We will unravel the protein content of pathological inclusions in neurons (figure B) collected after laser capture microdissection by mass spectrometry, and combine somatic genomic, and RNA sequencing data with proteomics data under the hypothesis that (epi-) genetic abnormalities are closely interrelated with disturbed protein interactions in such disease processes. B. We will determine the functional effects of potential SD DNM in cell and zebrafish models. The idea of somatic mutations, recently suggested as cause of neurodegenerative diseases, has hardly been investigated (Poduri et al., Science, 2013). A first limited step in the combined genetic-proteomic approach has proven to be successful in the discovery of the genetic defect of familial neurofilamentopathy (Wong et al., Brain, 2015). Besides being fundamentally interesting by itself, this new approach and concept opens a new area for Semantic Dementia, as a topographical confined disease process. Epigenetic changes are increasingly recognized as potential causative mechanisms, but focusing on the very local level of the temporal cortex is absolutely novel. The ultimate objectives of the current proposal are: • to generate a complete list of somatic DNMs identified in SD brains. • to identify SD-specific patterns of altered RNA expression in the dentate gyrus. • to obtain a list of proteins accumulated in the TDP43-positive inclusions, from which we can select candidate proteins by their correlation with somatic DNMs and/or altered gene expression. • to generate specific cellular or zebrafish models with impaired synaptic transmission and/or brain development reflecting he disease process in SD. • investigate the functional effects of somatic DNMs in cell and animal models, and to validate specific proteins as biomarkers in cerebrospinal fluid obtained from SD patients.