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

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• 作者：Assunta Senatore¹ ; ² ; Simona Colleoni³ ; Claudia Verderio⁴ ; Elena Restelli¹ ; ² ; Raffaella Morini⁴ ; Steven  ; B. Condliffe⁴ ; ⁷ ; Ilaria Bertani¹ ; ² ; Susanna Mantovani¹ ; ² ; Mara Canovi³ ; Edoardo Micotti² ; Gianluigi Forloni² ; Annette  ; C. Dolphin⁵ ; Michela Matteoli⁴ ; ⁶ ; Marco Gobbi³ ; Roberto Chiesa¹ ; ² ; ^{roberto.chiesa@marionegri.it}
• 刊名：Neuron
• 出版年：2012
• 期刊代码：45_08966273
• 类别：neu
• 出版时间：26 April, 2012
• 卷：74
• 期：2
• 页码：300-313
• 文件大小：2092 K

摘要

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Summary

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 伪₂未-1 subunit, which promotes the anterograde trafficking of the channel. Owing to ER retention of mutant PrP, 伪₂未-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.