NR ADQV
AU Dupuis,L.; Mbebi,C.; Gonzalez de Aguilar,J.L.; Rene,F.; Muller,A.; de Tapia,M.; Loeffler,J.P.
TI Loss of prion protein in a transgenic model of amyotrophic lateral sclerosis
QU Molecular and Cellular Neurosciences 2002 Feb; 19(2): 216-24
PT journal article
AB Amyotrophic lateral sclerosis (ALS) is a motor neuron degenerative disorder caused in a proportion of cases by missense mutations in the gene encoding Cu/Zn superoxide dismutase (Cu/Zn-SOD) which result in unknown, lethal enzymatic activity. Based on a differential screening approach, we show here that the gene encoding the cellular prion protein (PrPc) was specifically repressed in a transgenic model of ALS overexpressing the mutant G86R Cu/Zn-SOD. Analysis by Northern blot, semiquantitative RT-PCR, and Western blot revealed that PrPc down-regulation, which appeared early in the asymptomatic phase of the pathology, occurred preferentially in those tissues primarily affected by the disease (spinal cord, sciatic nerve, and gastrocnemius muscle). This down-regulation was not accompanied by refolding of the aberrant PrPsc isoform, the agent which causes transmissible spongiform encephalopathies. Furthermore, modification of PrPc expression was specifically linked to the presence of the G86R mutant since no changes were observed in transgenic mice overexpressing wild-type Cu/Zn-SOD. PrPc has been shown to play a role in the protection against oxidative stress, and we therefore propose that its down-regulation may contribute at least in part to ALS pathogenesis.
MH Amyotrophic Lateral Sclerosis/*genetics/metabolism/physiopathology; Animal; DNA Mutational Analysis; Disease Models, Animal; Down-Regulation/*genetics; Gene Library; Genetic Screening; Mice; Mice, Transgenic; Molecular Chaperones/genetics/metabolism; Muscle, Skeletal/metabolism; Mutation/*genetics; PrPc Proteins/*deficiency/genetics; Protein Folding; RNA, Messenger/metabolism; Sciatic Nerve/metabolism; Spinal Cord/metabolism; Superoxide Dismutase/*genetics/metabolism; Support, Non-U.S. Gov't
AD Laboratoire de Signalisations Moleculaires et Neurodegenerescence, EA 3433 Faculte de Medecine, Universite Louis Pasteur, Strasbourg, France.
SP englisch
PO USA