Molecular Mechanisms of Frontotemporal Lobar Degeneration

The aim of this thesis was to identify genetic factors involved in frontotemporal lobar degeneration (FTLD), a neurodegenerative disorder clinically characterised by a progressive change in personality, behaviour and language. FTLD is a genetically complex disorder and a positive family history is found in up to 40% of the cases. In 10-20% of the familial cases the disease can be explained by mutations in the gene encoding the microtubule associated protein tau (MAPT). In the first study we describe the clinical and neuropathological features of a Finnish family with FTLD caused by a mutation in MAPT. We also provide evidence that the pathogenic mechanism of this mutation is through altered splicing of MAPT transcripts. Recently, mutations in the gene encoding progranulin (PGRN) were identified as a major cause of FTLD. In the second study we describe a Swedish family with FTLD caused by a frameshift mutation in PGRN. We provide a clinical and neuropathological description of the family, as well as evidence that the pathogenicity of this mutation is through nonsense-mediated decay of the mutant mRNA transcripts and PGRN haploinsufficiency. In the third study we describe a novel PGRN splice site mutation and a previously described PGRN frameshift mutation, found in a mutation screen of 51 FTLD patients. We describe the clinical and neuropathological characteristics of the mutation carriers and demonstrate that haploinsufficiency is the pathogenic mechanism of the two mutations. In the fourth study we investigate the prevalence of PGRN and MAPT gene dosage alterations in 39 patients with FTLD. No gene dosage alterations were identified, indicating that variations in copy number of the PGRN and MAPT genes are not a common cause of disease, at least not in this FTLD patient collection.

Where do e-Government strategies take the Nordic nations?

An effective strategy is critical for the successful development of e-Government. The leading nations in the e-Government rankings include Sweden, Norway, Denmark and Finland. Their leading role makes them interesting to study when looking for reasons to successful e-Government. The purpose of this research paper is to describe the e-Government development strategies of Nordic countries, which rank highly on the international stage. In particular it aims to study the foci of these strategies. The approach is a document study of the e-Government development strategies of Sweden, Denmark, Norway and Finland was carried out using a qualitative content analysis inductive method. The results show that the major focus of Nordic e-Government strategies is on public sector reforms. Other focus areas include economic reforms and, to a lesser extent, e-Democracy efforts. Sweden, Finland and Norway have set ambitious policy goals in order to achieve global leadership in e-Government development. In response to the question posed by this paper’s title, we can say that Nordic e-Government strategies, except for Norway, focus more on reforming public sector services than on economic reforms.  E-Democracy reforms are hardly focused on at all. Practical implications: Public sector policy makers can relate their policy foci to some of the more successful e-Government countries in the world. Research implications/originality is that this paper can apart from the findings also provide a means on how to identify the actual foci of a country’s e-Government policy.