title: Mutant PrP suppresses glutamatergic neurotransmission in cerebellar granule neurons by impairing membrane delivery of VGCC α(2)δ-1 Subunit.
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(2)δ-1 subunit, which promotes the anterograde trafficking of the channel. Owing to ER retention of mutant PrP, α(2)δ-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.
authors.affiliation: Dulbecco Telethon Institute, 20156 Milan, Italy.
authors.forename: Assunta
authors.initials: A
authors.lastname: Senatore
authors.forename: Simona
authors.initials: S
authors.lastname: Colleoni
authors.forename: Claudia
authors.initials: C
authors.lastname: Verderio
authors.forename: Elena
authors.initials: E
authors.lastname: Restelli
authors.forename: Raffaella
authors.initials: R
authors.lastname: Morini
authors.forename: Steven B
authors.initials: SB
authors.lastname: Condliffe
authors.forename: Ilaria
authors.initials: I
authors.lastname: Bertani
authors.forename: Susanna
authors.initials: S
authors.lastname: Mantovani
authors.forename: Mara
authors.initials: M
authors.lastname: Canovi
authors.forename: Edoardo
authors.initials: E
authors.lastname: Micotti
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Forloni
authors.forename: Annette C
authors.initials: AC
authors.lastname: Dolphin
authors.forename: Michela
authors.initials: M
authors.lastname: Matteoli
authors.forename: Marco
authors.initials: M
authors.lastname: Gobbi
authors.forename: Roberto
authors.initials: R
authors.lastname: Chiesa
mesh_terms: D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D001703:Biophysics; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000378:metabolism*; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology*; D004195:Disease Models, Animal; D004558:Electric Stimulation; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D008279:Magnetic Resonance Imaging; D008564:Membrane Potentials / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009043:Motor Activity / Q000235:genetics; D009154:Mutation / Q000235:genetics*; D009474:Neurons / Q000378:metabolism* / Q000648:ultrastructure; D018408:Patch-Clamp Techniques; D017096:Prion Diseases / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D000072002:Prion Proteins; D011328:Prions / Q000235:genetics*; D021381:Protein Transport / Q000235:genetics; D011930:Reaction Time / Q000235:genetics; D045442:Rotarod Performance Test; D009435:Synaptic Transmission / Q000235:genetics*; D013574:Synaptosomes / Q000378:metabolism
chemical_list: C553974:CACNA2D3 protein, mouse; D015220:Calcium Channels; D000072002:Prion Proteins; D011328:Prions; C512657:Prnp protein, mouse; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D018698:Glutamic Acid; D002118:Calcium