Animal model and molecular interactions of Cln5

Neuronal ceroid lipofuscinoses (NCLs) are a family of inherited pediatric neurodegenerative disorders, leading to retinal degeneration, death of selective neuronal populations and accumulation of autofluorscent ceroid-lipopigments. The clinical manifestations are generally similar in all forms. The Finnish variant late infantile neuronal ceroid lipofuscinosis (vLINCLFin) is a form of NCL, especially enriched in the Finnish population. The aim of this thesis was to analyse the brain pathology of vLINCLFin utilising the novel Cln5-/- mouse model. Gene expression profiling of the brains of already symptomatic Cln5-/- mice revealed that inflammation, neurodegeneration and defects in myelinization are the major characteristics of the later stages of the disease. Histological characterization of the brain pathology confirmed that the thalamocortical system is affected in Cln5-/- mice, similarly to the other NCL mouse models. However, whereas the brain pathology in all other analyzed NCL mice initiate in the thalamus and spread only months later to the cortex, we observed that the sequence of events is uniquely reversed in Cln5-/- mice; beginning in the cortex and spreading to the thalamus only months later. We could also show that even though neurodegeneration is inititated in the cortex, reactive gliosis and loss of myelin are evident in specific nuclei of the thalamus already in the 1 month old brain. To obtain a deeper insight into the disturbed metabolic pathways, we performed gene expression profiling of presymptomatic mouse brains. We validated these findings with immunohistological analyses, and could show that cytoskeleton and myelin were affected in Cln5-/- mice. Comparison of gene expression profiling results of Cln5-/- and Cln1-/- mice, further highlighted that these two NCL models share a common defective pathway, leading to disturbances in the neuronal growth cone and cytoskeleton. Encouraged by the evidence of this defected pathway, we analyzed the molecular interactions of NCL-proteins and observed that Cln5 and Cln1/Ppt1 proteins interact with each other. Furthermore, we demonstrated that Cln5 and Cln1/Ppt1 share an interaction partner, the F1-ATP synthase, potentially linking both vLINCLFIN and INCL diseases to disturbed lipid metabolism. In addition, Cln5 was shown to interact with other NCL proteins; Cln2, Cln3, Cln6 and Cln8, implicating a central role for Cln5 in the NCL pathophysiology. This study is the first to describe the brain pathology and gene expression changes in the Cln5-/- mouse. Together the findings presented in this thesis represent novel information of the disease processes and the molecular mechanisms behind vLINCLFin and have highlighted that vLINCLFin forms a very important model to analyze the pathophysiology of NCL diseases.

The Population Consequences of Sex and Conflict

Natural selection generally operates at the level of the individual, or more specifically at the level of the gene. As a result, individual selection does not always favour traits which benefit the population or species as a whole. The spread of an individual gene may even act to the detriment of the organism in which it finds. Thus selection at the level of the individual can affect processes at the level of the organism, group or even at the level of the species. As most behaviours ultimately affect births, deaths and the distribution of individuals, it seems inevitable that behavioural decisions will have an impact on population dynamics and population densities. Behavioural decisions can often involve costs through allocation of energy into behavioural strategies, such as the investment into armaments involved in fighting over resources or increased mortality due to injury or increased predation risk. Similarly, behaviour may act o to benefit the population, in terms of higher survival and increased fecundity. Examples include increased investment through parental care, choosing a mate based on the nuptial gifts they may supply and choosing territories in the face of competition. Investigating the impact of behaviour on population ecology may seem like a trivial task, but it is likely to have important consequences at different levels. For example, antagonistic behaviour may occasionally become so extreme that it increases the risk of extinction, and such extinction risk may have important implications for conservation. As a corollary, any such behaviour may also act as a macroevolutionary force, weeding out populations with traits which, whilst beneficial to the individuals in the short term, ultimately result in population extinction. In this thesis, I examine how behaviours, specifically conflict and competition over a resource and aspects of behaviour involved in sexual selection, can affect population densities, and what the implications are for the evolution and ecology of the populations in question. It is found that both behaviours related to individual conflict and mating strategies can have an effect at the level of the population, but that various factors, such as a feedback between selection and population densities or macroevolution caused by species extinctions, may act to limit the intensity of conflicts that we observe in nature.

Cattle Teeth in Graves : Interpretations of animal bones found in Finnish inhumation graves (ca AD 550-1700)

The nature of a burial is always ritualistic. This is often forgotten when dealing with Finnish inhumation burials containing animal bones. Only the animal bones found close to the deceased have traditionally been thought to have a ritualistic purpose. The animal bones found in the filling of the grave, which is still part of the burial, has on the other hand, often been neglected in the previous research. In this Master s thesis I will discuss the function and interpretation of animal bones in graves. The base of this study is six sites, all of different nature, from Finland. Luistari in Eura is from the western coast and is dated to Late Iron Age (and possibly Medieval period), the Medieval hamlet of Finno is situated in Espoo which is situated on the southern coast. Two town burials, Turku and Porvoo, are also included in this study. The graves from Turku are dated to Late Medieval period and Early Renaissance, whereas the cemetery in Porvoo is from the 18th century. Visulahti in Mikkeli is from the Late Iron Age and represents Eastern Finnish burial tradition, the same as Suotniemi from Käkisalmi parish, which is nowadays part of Russia. While parts of the animal bones had already been analysed before, the author also analysed animal bones for the purpose of the present Master´s thesis. The bones were compared to the burial contexts, when possible. Based on the comparisons I have made interpretations which might explain the existence of animal bones in the graves. The interpretations are among others sacrifice, commemoration meals and animal burials. The site could also have been a settlement site prior to the graves, thus the bones in the graves would belong to the settlement phase. When comparing the date of the studied sites, the town burials are later and the animal bones are probably related to previous or contemporary use of the sites as graveyards. On top of this there does not seem to be much difference in burial tradition between Eastern and Western Finland, although at least from the hamlet burials of Finno there are aspects that could be linked to Eastern burials. In making the interpretations I have taken into consideration the aspects of belief during different time periods when they could be accounted as relevant. Also the problems with bone preservation were relevant and challenging for the study. Often only the hardest substance of the skeleton, namely teeth, has been preserved. For this reason the quality of the archaeological documentation was a key issue in this study. In producing quality interpretations of the animal bones in graves, the bones, contexts and their relationship to the surrounding site should be documented with care.