PRION DISEASES AND COPPER METABOLISM
CONTENTS 1 INTRODUCTION 2 NEUROPATHOLOGY OF TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHIES (PRION DISEASES) 3 CENTRAL PATHOGENESIS OF PRION DISEASES ¨ 4 HEREDITARY PRION PROTEIN AMYLOIDOSES 5 MOUSE BEHAVIOURAL STUDIES AND WHAT THEY CAN TEACH US ABOUT PRION DISEASES 6 ELECTROPHYSIOLOGICAL APPROACHES TO THE STUDY OF PRION DISEASES 7 PRION PROTEIN, PRION PROTEIN-LIKE PROTEIN, AND NEURODEGENERATION 8 OXIDATIVE STRESS AND MITOCHONDRIAL DYSFUNCTION IN NEURODEGENERATION OF TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHIES (TSES) 9 MECHANISMS OF PRION TOXICITY AND THEIR RELATIONSHIP TO PRION INFECTIVITY 10 A STONE GUEST ON THE BRAIN: DEATH AS A PRION 11 MOLECULAR MECHANISMS MEDIATING NEURONAL CELL DEATH IN EXPERIMENTAL MODELS OF PRION DISEASES, IN VITRO 12 PROCESSING AND MIS-PROCESSING OF THE PRION PROTEIN: INSIGHTS INTO THE PATHOGENESIS OF FAMILIAL PRION DISORDERS 13 SIGNALING PATHWAYS CONTROLING PRION NEUROTOXICITY: ROLE OF ENDOPLASMIC RETICULUM STRESS-MEDIATED APOPTOSIS 14 CELL CULTURE MODELS TO UNRAVEL PRION PROTEIN FUNCTION AND ABERRANCIES IN TSE 15 INSIGHTS INTO THE CELLULAR TRAF?CKING OF PRION PROTEINS 16 THE MOLECULAR BASIS OF PRION PROTEIN-MEDIATED NEURONAL DAMAGE 17 CONCLUSION: INTERVENTION, THE ?NAL FRONTIER CHAPTER INTRODUCTION IN 1982 STANLEY PRUSINER AND COLLEAGUES PURI?ED AN ABNORMAL PROTEIN FROM THE BRAINS OF MICE EXPERIMENTALLY INFECTED WITH A RARE SHEEP DIS- EASE CALLED SCRAPIE1 THIS PROTEIN WAS CALLED THE PRION PROTEIN EARLIER WORK HAD SUGGESTED THAT THIS DISEASES AND OTHERS, LOOSELY COLLECTED TO- GETHER AS TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHIES (TSES), WERE NOT TRANSMITTED BY CONVENTIONAL INFECTIOUS AGENTS PRUSINER SUGGESTED THAT THIS NEW PROTEIN WAS THE INFECTIOUS AGENT IN THESE DISEASES2 SUCH A CONTENTIOUS SUGGESTION LEAD TO FEROCIOUS DEBATE MANY RESEARCHERS STILL MAINTAINED THAT THERE WAS NO SUCH THING AS AN INFECTIOUS PROTEIN DE- SPITE THIS, BY 1990 MOST PEOPLE ACCEPTED THAT THE CAUSE OF THE TSES WAS THE ABNORMAL ISOFORM OF THE PRION PROTEIN HIS RESEARCH GROUP HAD IDEN- TI?ED THE MOST CONVINCING EVIDENCE FOR THIS HAD COME FROM THE WORK OF CHARLES WEISSMANN, WHOSE PRION PROTEIN KNOCKOUT MICE COULD NOT BE INFECTED BECAUSE THEY LACKED EXPRESSION OF THE PROTEIN THAT WAS NOW FOREVER LINKED TO THESE DISEASE3,4 SINCE THEN IT HAS BECOME MORE WIDELY ACCEPTED FOR THESE DISEASES TO BE TERMED PRION DISEASES IN 1997 WHEN STANLEY PRUSINER WON THE NOBEL PRIZE FOR HIS WORK ON PRION DISEASES5 EVEN THEN, THERE WAS STILL AN ELEMENT OF RESISTANCE IN THE SCIENTI?C COM- MUNITY IT WAS CONSIDERED THAT, IN ORDER THE TRANSMISSIBLE AGENT TO TRULY BE A PROTEIN ONLY, THE PROTEIN WOULD HAVE TO BE GENERATED FROM A RECOM- BINANT SOURCE IN 2004 THAT EVIDENCE EMERGED RECOMBINANT PROTEIN INJECTED INTO MICE LED TO A PRION DISEASE THAT COULD THEN BE TRANSMITTED TO OTHER MICE6 NATURALLY, SCEPTICISM STILL CONTINUES ABOUT THIS NOVEL THEORY THOSE WHO WORK IN THE PRION ?ELD KNOW THAT THIS IS SIMPLY PART OF THE GAME INTENSE