Generation of a Medaka Fish Model of Propionic Acidemia for Development of Novel Therapies

............................................................................................................................................... 3 List of abbreviations............................................................................................................................. 5 Introduction .......................................................................................................................................... 6 Propionic acidemia.......................................................................................................................... 6 Pathogenesis of PA ......................................................................................................................... 9 Treatment strategies for PA: state of the art ................................................................................ 11 Animal models of PA .................................................................................................................... 13 Open research questions and unmet medical needs .................................................................... 14 Aims of the project ............................................................................................................................. 16 Methods .............................................................................................................................................. 17 Animal strain and maintenance ................................................................................................... 17 Generation of PA medaka ............................................................................................................. 17 Phenotyping of PA medaka fishes ................................................................................................ 19 Pccb protein studies....................................................................................................................... 20 Biochemical analysis ..................................................................................................................... 21 Behavioral analysis ....................................................................................................................... 21 Treatments on affected larvae ...................................................................................................... 22 Drug screening .............................................................................................................................. 22 Statistical analyses ........................................................................................................................ 23 Results ................................................................................................................................................ 24 Generation of PA medaka ............................................................................................................. 24 Phenotyping of pccb del/del medaka ................................................................................................. 25 Biochemical analysis ..................................................................................................................... 30