Abstract
Frontotemporal lobar degeneration (FTLD) is a clinical, pathological and genetically heterogeneous disease representing 10-20% of all dementias. Despite significant progress in our understanding of FTLD in the last two decades, deep mechanistic insight into the biological processes underlying FTLD are still lacking and no treatment for FTLD exists. At least 3 forms of FTLD are defined based on the specific pathological protein that accumulates in a patient's brain. The most common form is FTLD-TDP, characterized by the accumulation of TAR DNA-binding protein 43 (TDP-43). This accumulation and loss of function of TDP-43 causes dysfunctions in the process of maturation of the messenger RNAs (mRNAs) from their premature forms, called splicing. In this project we aim to identify alternative splicing events associated with FTLD-TDP. To do so, we will sequence all the sets of mRNAs (transcripts) of brains of FTLD-TDP patients and controls with the newest technology (long-read sequencing). As such, we will generate the first set of data of this kind in FTLD-TDP. Candidate transcripts that appear to be significantly altered in FTLD-TDP brains as compared to controls will be further selected and analyzed in additional FTLD-TDP patients and controls and in patients with related pathologies (Alzheimer's disease, FTLD-Tau) to determine the specificity of these alterations. We will also examine the localization and organization of these transcripts within the affected brain region. This project will provide more knowledge about the biological processes that occur in FTLD-TDP, suggesting new biomarker candidates and targets for the development of therapies for this disease.
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