Assessing the role of copy number variations, mitochondrial DNA and microRNAs in neurodegenerative disorders.

Student thesis: Doctoral thesis


Neurodegenerative diseases are complex and progressive disorders that affect millions of people worldwide. Among them, Alzheimer’s disease (AD), Parkinson’s disease (PD) and frontotemporal dementia (FTD) are three of the most prevalent. In spite of extensive research, the molecular events triggering these pathologies remain elusive. This thesis aims at understanding the role of certain genetic and epigenetic factors in neurodegenerative diseases through the study of structural genetic rearrangements, and the measurement of circulating mitochondrial DNA and non-coding RNA species. We first analyzed the structural variation pattern of the chromosome 17q21.31, one of the most complex and dynamic regions of the human genome, and evaluated its contribution to the well-established MAPT H1 haplotype relationship with PD, progressive supranuclear palsy (PSP), corticobasal degeneration (CBD) and dementia with Lewy bodies (DLB). Our results suggest that copy number polymorphisms within this region are not responsible for the H1 effect. However, we found a significant overrepresentation of H1 carriers in DLB patients, thus expanding the biological relevance of the haplotype in neurodegenerative disorders. We also examined the levels of circulating cell-free mitochondrial DNA in cerebrospinal fluid (CSF) and its utility as an indicator of mitochondrial dysfunction in the AD continuum. Although its measurement is reliable, the considerable inter-individual variability within groups limits its accuracy and usefulness as a diagnostic biomarker. Finally, we investigated the expression profile of microRNAs, a class of non-coding RNAs involved in the post-transcriptional modulation of gene expression, contained in extracellular vesicles (EVs) from CSF in FTD and other related syndromes. Numerous microRNAs can be detected within EVs from CSF. Moreover, we identified four microRNAs with a specific expression pattern in patients diagnosed with 4R-tau FTD syndromes.
Date of Award13 Sept 2019
Original languageEnglish
SupervisorAlberto Lleo Bisa (Tutor) & Jordi Clarimon Echavarria (Director)

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