Mutant PrP Suppresses Glutamatergic Neurotransmission in Cerebellar Granule Neurons by Impairing Membrane Delivery of VGCC α 2δ-1 Subunit

Assunta Senatore, Simona Colleoni, Claudia Verderio, Elena Restelli, Raffaella Morini, Steven B. Condliffe, Ilaria Bertani, Susanna Mantovani, Mara Canovi, Edoardo Micotti, Gianluigi Forloni, Annette C. Dolphin, Michela Matteoli, Marco Gobbi, Roberto Chiesa

Research output: Contribution to journalArticlepeer-review

Abstract

How mutant prion protein (PrP) leads to neurological dysfunction in genetic prion diseases is unknown. Tg(PG14) mice synthesize a misfolded mutant PrP which is partially retained in the neuronal endoplasmic reticulum (ER). As these mice age, they develop ataxia and massive degeneration of cerebellar granule neurons (CGNs). Here, we report that motor behavioral deficits in Tg(PG14) mice emerge before neurodegeneration and are associated with defective glutamate exocytosis from granule neurons due to impaired calcium dynamics. We found that mutant PrP interacts with the voltage-gated calcium channel α 2δ-1 subunit, which promotes the anterograde trafficking of the channel. Owing to ER retention of mutant PrP, α 2δ-1 accumulates intracellularly, impairing delivery of the channel complex to the cell surface. Thus, mutant PrP disrupts cerebellar glutamatergic neurotransmission by reducing the number of functional channels in CGNs. These results link intracellular PrP retention to synaptic dysfunction, indicating new modalities of neurotoxicity and potential therapeutic strategies. How mutant prion protein causes neurological dysfunction in genetic prion diseases is not fully known. Senatore et al. report intracellular accumulation of misfolded prion impairs voltage-gated calcium channel transport to synapses, altering glutamatergic neurotransmission and cerebellum-dependent motor function.

Original languageEnglish
Pages (from-to)300-313
Number of pages14
JournalNeuron
Volume74
Issue number2
DOIs
Publication statusPublished - Apr 26 2012

ASJC Scopus subject areas

  • Neuroscience(all)

Fingerprint

Dive into the research topics of 'Mutant PrP Suppresses Glutamatergic Neurotransmission in Cerebellar Granule Neurons by Impairing Membrane Delivery of VGCC α 2δ-1 Subunit'. Together they form a unique fingerprint.

Cite this