Influence of base-excision-repair pathway enzymes on prion pathogenesis
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Experimental prion disease in mice is a well-established model system for studying the pathogenesis of prion-induced neurodegeneration. The mouse-adapted Rocky Mountain Laboratories (RML) strain is commonly used for this purpose. With the ever-increasing catalogue of transgenic mice in which one or more genes have been invalidated, a considerable number of studies of prion disease have been performed in knockout lines, in search for genes that could influence the disease progression and presentation. The general idea behind such studies is to gain knowledge of the pathogenesis and to identify new targets for disease treatment and/or prevention. This is indeed also the foundation of the studies in this thesis. We have asked the question; do DNA repair enzymes belonging to the base-excision-repair (BER) pathway contribute cellular protection against prion-induced toxicity? To explore this, we have used three relatively newly developed lines of BER-enzyme knockouts. Although some of the physiological roles of the individual BER enzymes have been established, the full spectrum of functions are still very much under investigation. Thus, the studies in this thesis have also had this aspect in mind¬¬¬—namely that experimental prion disease in these mouse models could potentially reveal less explored functions of these enzymes. Three lines of transgenic mice with compromised BER-enzyme activity were subjected to RML prion disease, and in two of our studies (Paper II and III) samples were analyzed both at onset and end-stage of disease. The most striking observations from these studies are that the pre-clinical progression of experimental prion disease appears largely unaffected by BER-enzyme activities. However, loss of BER enzymes in all three models used resulted in a more dramatic and shortened clinical (toxic) phase of the disease, suggesting that BER-enzyme activity in various ways contributes neuronal protection in the final clinical phase. Taken together, one could, based upon our results, reach the conclusion that BER repair of oxidative DNA damage in prion disease is of moderate or minor importance. It should, however, be noted that the model we have used, with intracerebral inoculation of RML prions, is a brutally efficient disease model, resulting in a disease progression that barely is affected by any genetic or other intervention. When taking this aspect into consideration, our observations of significantly shortened clinical duration in the absence of different BER activities, to my mind, indicates that these DNA repair enzymes play a significant part in anti-prion neuroprotection.