Analysis of the cerebellar proteome in a transgenic mouse model of inherited prion disease reveals preclinical alteration of calcineurin activity.
Inherited prion diseases are linked to insertional and point mutations in the prion protein (PrP) gene, which favor conversion of PrP into a conformationally altered, pathogenic isoform. The cellular mechanism by which this process causes neurological dysfunction is unknown. Transgenic (Tg) (PG14) mice express a mouse PrP homolog of a nine-octapeptide insertion associated with an inherited prion disorder. These mice develop a progressive neurological syndrome characterized by ataxia and cerebellar atrophy due to synaptic degeneration in the molecular layer and massive apoptosis of granule neurons. To investigate the molecular events that may contribute to neurological dysfunction, we carried out a differential proteomic analysis of cerebella from Tg(PG14) mice at the preclinical, onset, and symptomatic phases of their neurological illness. 2-D maps of cerebellar proteins from Tg(PG14) mice were compared to those obtained from age-matched Tg(WT) mice that express wild-type PrP and remain healthy. Proteins whose levels were significantly modified in at least one stage of the Tg(PG14) disease were identified by PMF. Analysis detected a preclinical decrease of the calcium/calmodulin-dependent phosphatase calcineurin (CaN) in granule neurons, suggesting that dysregulation of CaN activity induced by mutant PrP may be responsible for the cerebellar dysfunction in Tg(PG14) mice.
Prion Unit, Dulbecco Telethon Institute, Istituto di Ricerche Farmacologiche Mario Negri, Via Eritrea, Milano, Italy.
Emiliano
E
Biasini
Tania
T
Massignan
Luana
L
Fioriti
Valentina
V
Rossi
Sara
S
Dossena
Mario
M
Salmona
Gianluigi
G
Forloni
Valentina
V
Bonetto
Roberto
R
Chiesa
D000818:Animals; D019703:Calcineurin / Q000032:analysis / Q000378:metabolism*; D002531:Cerebellum / Q000737:chemistry* / Q000378:metabolism*; D004195:Disease Models, Animal; D018450:Disease Progression; D015536:Down-Regulation; D004789:Enzyme Activation; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000737:chemistry / Q000378:metabolism; D017096:Prion Diseases / Q000235:genetics / Q000378:metabolism*; D020543:Proteome / Q000737:chemistry*
D020543:Proteome; D019703:Calcineurin