Analysis of the cerebellar proteome in a transgenic mouse model of inherited prion disease reveals preclinical alteration of calcineurin activity

Emiliano Biasini, Tania Massignan, Luana Fioriti, Valentina Rossi, Sara Dossena, Mario Salmona, Gianluigi Forloni, Valentina Bonetto, Roberto Chiesa

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)2823-2834
Number of pages12
JournalProteomics
Volume6
Issue number9
DOIs
Publication statusPublished - May 2006

Fingerprint

Prion Diseases
Calcineurin
Prions
Proteome
Transgenic Mice
Neurons
Proteins
Cerebellar Diseases
Calmodulin
Cerebellar Ataxia
Mutant Proteins
Protein Isoforms
Point Mutation
Proteomics
Cerebellum
Atrophy
Apoptosis
Calcium
Prion Proteins
Genes

Keywords

  • Cerebellum
  • Neurodegeneration
  • Prion
  • Synapse
  • Transgenic

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics

Cite this

Analysis of the cerebellar proteome in a transgenic mouse model of inherited prion disease reveals preclinical alteration of calcineurin activity. / Biasini, Emiliano; Massignan, Tania; Fioriti, Luana; Rossi, Valentina; Dossena, Sara; Salmona, Mario; Forloni, Gianluigi; Bonetto, Valentina; Chiesa, Roberto.

In: Proteomics, Vol. 6, No. 9, 05.2006, p. 2823-2834.

Research output: Contribution to journalArticle

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