Multiple deletions in mtDNA give rise to a variety of neuromuscular symptoms, often associated with genetic inherited disorders and aging and they have been reported in patients with neurodegenerative diseases, such as Parkinson’s and Alzheimer’s diseases. In spite of its medical importance, not much is yet known about the mechanisms by which mtDNA deletions are formed. Progressive external ophtalmoplegia (PEO) is one of the conditions characterized by the accumulation of mtDNA deletions. This disease is caused by mutations in components of the mtDNA replication machinery, like the DNA polymerase γ (POLγ) and the replicative helicase TWINKLE. Recently, also the helicase-nuclease DNA2 has been found mutated in patients affected by this disorder. The precise function of human DNA2 (hDNA2) has remained elusive. hDNA2 localizes to mitochondria and has the biochemical properties to process four-stranded DNA structure (G-quadruplexes). Interestingly, G-quadruplex DNA associates with mtDNA deletions formation in human diseases. To dissect the mitochondrial role of hDNA2, I will focus on the mechanism of hDNA2 recruitment to mtDNA. Then I will address the role of DNA2 in mitochondria metabolism and in G-quadruplexes mtDNA metabolism and I will characterize the consequences of disease-associated mutations in DNA2 gene. I will employ a range of in vitro (based on recombinant protein) and in vivo (inducible cell systems and yeast model). The clarification of the hDNA2 mitochondrial biological function will help to elucidate the mechanism by which mtDNA deletions are formed in mitochondrial disorders. Moreover, MITOQUAD project will lead to a deeper understanding of how mtDNA integrity is maintained, a relevant question for understanding the early development and progress of a large number of mitochondrial disorders, in order to treat or prevent their occurrence.
In Europe today disabled people comprise some 65 million (10%). Yet they are marginalized in society and research, and little is known on how disabilities become liveable. This project challenges this bias by proposing to investigate ‘liveable disabilities’ as a function of disability and opportunity structures across time. It analyses four life course dimensions: disabled people’s (1) health and well-being; (2) involvement in education and work; (3) in a partner relationship and family; and (4) in leisure structures. Through this I identify liveable disabilities before, during and after the Swedish welfare state. The results are of significant cross-national interest as they form a useful baseline for what constitutes liveable disabilities, which helps governing bodies maximize opportunity structures for disabled people to participate fully in society. This proposal is unique in employing mixed-methods life course research across time. First, it involves quantitative analysis of Sweden’s long-term digitized population databases, which reflect how disability impacts on people’s educational, occupational, marital and survival chances. The statistical outcome is novel in demonstrating how different impairments intersect with human characteristics relative to society’s structures of the past 200 years. Second, qualitative analyses uncover how disabled people today experience and talk about the above dimensions (1-4) themselves, and how mass media depict them. Third, I make innovative studies of leisure structures, which may promote liveable disabilities. The proposal aims to establish me at the forefront of disability research. It benefits from my scholarship in history and demography and from three excellent centres at Umeå University I am connected to, funded by the Swedish Research Council. One centre researches populations, another gender. The third provides expertise in disability studies and ready access to stakeholders outside academia.