title: Infection of metallothionein 1+2 knockout mice with Rocky Mountain Laboratory scrapie.
abstract: Metallothioneins (MT) are heavy metal-binding, antioxidant proteins with relevant roles described in many pathological conditions affecting the central nervous system (CNS). Regarding prion diseases, a number of publications demonstrate an up-regulation of MT-1+2 in the brains of TSE affected cattle, humans and experimentally inoculated rodents. Since the prion protein also binds copper, and oxidative stress is one of the events presumably triggered by PrPsc deposition, it seems plausible that MTs have a relevant role in the outcome of these neurodegenerative processes. To gain knowledge of the role of MTs in TSE pathogeny, and particularly of that of MT-1+2, a transgenic MT-1+2 knockout mouse model (MT-1+2 KO) was intracerebrally inoculated with the mouse-adapted Rocky Mountain Laboratory (RML) strain of scrapie; 129SvJ mice were used as controls (WT). Clinical signs were monitored and animals were humanely sacrificed when they scored positive clinically. Brains were fixed following intracardiac perfusion with 4% formaldehyde, paraffin embedded, and processed for histological, histochemical and immunohistochemical evaluation. The incubation period did not show significant differences between MT-1+2 KO and WT mice, nor did the evolution of neurological signs. Upon neuropathological characterisation of the brains, moderate differences were observed in astroglial and microglial response, spongiosis score and PrPsc deposition, particularly in brain regions to which the studied strain showed a stronger tropism (i.e. hippocampus). Results showed that the brain defence mechanisms against PrPsc deposition involve, aside from MT-1+2, other molecules, such as HSP25, which are capable of compensating for the lack of MT-1+2.
authors.affiliation: Priocat Laboratory, CReSA, Autonomous University of Barcelona, 08193 Bellaterra (Cerdanyola del Vallès), Spain. enric.vidal@cresa.uab.cat
authors.forename: Enric
authors.initials: E
authors.lastname: Vidal
authors.forename: Raül
authors.initials: R
authors.lastname: Tortosa
authors.forename: Mercedes
authors.initials: M
authors.lastname: Márquez
authors.forename: Anna
authors.initials: A
authors.lastname: Serafin
authors.forename: Juan
authors.initials: J
authors.lastname: Hidalgo
authors.forename: Martí
authors.initials: M
authors.lastname: Pumarola
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000378:metabolism; D008668:Metallothionein / Q000172:deficiency*; D051379:Mice; D018345:Mice, Knockout; D037121:Plant Lectins; D011328:Prions / Q000235:genetics* / Q000378:metabolism / Q000472:pathogenicity*; D012608:Scrapie / Q000235:genetics* / Q000473:pathology; D018709:Statistics, Nonparametric
chemical_list: D005904:Glial Fibrillary Acidic Protein; D006360:Heat-Shock Proteins; D037121:Plant Lectins; D011328:Prions; C034981:tomato lectin; D008668:Metallothionein