Tandem Repeats Associated with Neurogenomic Somatic Instability and Neurodegeneration

Objective

"Dementia and other neurodegenerative diseases are among the leading causes of disability worldwide and have an immense societal impact due to lack of effective treatments. For developing better preventive and therapeutic strategies, it is essential to clarify their still largely elusive genetic basis and pathophysiology. Emerging insights from the study of rare hereditary repeat expansion disorders caused by elongations of repetitive DNA sequences (""tandem repeats"" (TRs)) indicate that TRs could induce instability of neuronal DNA (""neurogenomic somatic instability""), and thereby instigate molecular changes that lead to neuronal degeneration. However, the role of highly prevalent TR variations or their somatic instability in the pathogenesis of common age-associated neurodegenerative diseases is unknown. Here, I aim to assess the role of TRs and their somatic instability in the pathogenesis of neuronal degeneration, the defining hallmark of all neurodegenerative diseases. To this end, I will 1) systematically identify TRs whose size or somatic instability are related to neuronal degeneration in the general population and/or disease severity in repeat expansion disorders, using an innovative approach combining ""liquid biopsy"" of neuronal tissue, high-throughput ultra-deep long-read DNA sequencing and ultrasensitive biomarkers of neuronal degeneration, 2) delineate the neuroanatomical pathways affected by TR somatic instability through comprehensive neuroimaging analyses, and 3) disentangle the underlying molecular and cellular mechanisms, using an extensive integrative multi-omics approach with experimental validation in neuronal cell lines and post-mortem human brain tissue. The wealth of unique insights from TRANSIT-ND could substantially increase our understanding of the pathogenesis of neuronal degeneration and provide shared targets for the prevention and treatment of a range of different neurodegenerative diseases that afflict millions of people globally."

Fields of science (EuroSciVoc)

CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: https://op.europa.eu/en/web/eu-vocabularies/euroscivoc.

• natural sciences biological sciences neurobiology
• natural sciences biological sciences genetics DNA
• medical and health sciences basic medicine physiology pathophysiology
• medical and health sciences basic medicine neurology dementia

Keywords

Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)

• neuroepidemiology
• genetic epidemiology
• neurodegenerative diseases
• tandem repeats
• repeat expansion disorders
• Huntington disease
• spinocerebellar ataxia
• somatic instability
• genetic association study

Host institution

Beneficiaries (1)