Abstract
Frontotemporal lobar degeneration (FTLD) is an umbrella term that groups several different neurodegenerative diseases characterized by the predominant destruction of the frontal and temporal lobes of the brain. In this proposal we focus our efforts on a relatively rare subgroup of FTLD patients which have an unusual clinical phenotype and a uniform pathology characterized by FTLD with neuronal inclusions composed of the fused in sarcoma (FUS) protein (FTLD-FUS). More than a decade after its initial description no progress has been made towards understanding the etiology of this subgroup of patients, thus severely hampering translational research efforts. To fill this void, we established the international consortium on FTLD-FUS. Through the systematic collection of brain tissue samples and associated clinicopathological data from the majority of reported FTLD-FUS patients we will for the first time be in a position to decipher its molecular underpinnings. Based on its unique clinical and pathological features, we hypothesize that FTLD-FUS is caused by genomic or epigenomic mutations in one or a limited number of disease genes. The overall objective of this proposal is to identify these genetic and/or epigenetic factors through the study of our unique, highly characterized, cohort of FTLD-FUS patient samples and state-of the art methodologies able to capture a broad range of possible genomic and epigenomic alterations. This will include NanoNOMeseq to identify phased methylation and chromatin accessibility as well as genetic changes such as structural variations from a single assay. Deep transcriptomic profiling at the single cell level and bulk analyses of full-length transcripts using long-read sequencing technologies in brain tissues of FTLD-FUS patients and controls will further be generated to correlate expression changes with possible disease-contributing variants and to provide much needed insights into the FTLD-FUS associated disease pathways. The identification of disease causing or disease modifying factors for FTLD-FUS will be crucial for elucidating the pathogenetic mechanisms underlying this subgroup of FTLD patients and ultimately for the development of curative therapies.
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