Alessandro Tozzi1, Antonio de Iure2, Vincenza Bagetta3, Michela Tantucci2, Valentina Durante2, Ana Quiroga-Varela2, Cinzia Costa2, Massimiliano Di Filippo2, Veronica Ghiglieri4, Emanuele Claudio Latagliata5, Michal Wegrzynowicz6, Mickael Decressac7, Carmela Giampà3, Jeffrey W Dalley8, Jing Xia8, Fabrizio Gardoni9, Manuela Mellone9, Omar Mukhtar El-Agnaf10, Mustafa Taleb Ardah10, Stefano Puglisi-Allegra5, Anders Björklund7, Maria Grazia Spillantini6, Barbara Picconi3, Paolo Calabresi11. 1. Department of Experimental Medicine, University of Perugia, Perugia; Fondazione Santa Lucia, Institutes for Research, Hospitalization and Health Care, Rome. 2. Department of Medicine, Hospital Santa Maria della Misericordia, Neurological Clinic, University of Perugia, Perugia. 3. Fondazione Santa Lucia, Institutes for Research, Hospitalization and Health Care, Rome. 4. Fondazione Santa Lucia, Institutes for Research, Hospitalization and Health Care, Rome; Department of Philosophy, Human, Social, and Educational Sciences, University of Perugia, Perugia. 5. Fondazione Santa Lucia, Institutes for Research, Hospitalization and Health Care, Rome; Department of Psychology, "Daniel Bovet" Centre, University of Rome "La Sapienza", Rome, Italy. 6. Department of Clinical Neurosciences, Cambridge Centre for Brain Repair, University of Cambridge, Cambridge, United Kingdom. 7. Department of Experimental Medical Sciences, Wallenberg Neuroscience Center, Lund University, Lund, Sweden. 8. Department of Psychology and Department of Psychiatry, Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, United Kingdom. 9. Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy. 10. Department of Biochemistry, Faculty of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates. 11. Fondazione Santa Lucia, Institutes for Research, Hospitalization and Health Care, Rome; Department of Medicine, Hospital Santa Maria della Misericordia, Neurological Clinic, University of Perugia, Perugia. Electronic address: paolo.calabresi@unipg.it.
Abstract
BACKGROUND: Advanced Parkinson's disease (PD) is characterized by massive degeneration of nigral dopaminergic neurons, dramatic motor and cognitive alterations, and presence of nigral Lewy bodies, whose main constituent is α-synuclein (α-syn). However, the synaptic mechanisms underlying behavioral and motor effects induced by early selective overexpression of nigral α-syn are still a matter of debate. METHODS: We performed behavioral, molecular, and immunohistochemical analyses in two transgenic models of PD, mice transgenic for truncated human α-synuclein 1-120 and rats injected with the adeno-associated viral vector carrying wild-type human α-synuclein. We also investigated striatal synaptic plasticity by electrophysiological recordings from spiny projection neurons and cholinergic interneurons. RESULTS: We found that overexpression of truncated or wild-type human α-syn causes partial reduction of striatal dopamine levels and selectively blocks the induction of long-term potentiation in striatal cholinergic interneurons, producing early memory and motor alterations. These effects were dependent on α-syn modulation of the GluN2D-expressing N-methyl-D-aspartate receptors in cholinergic interneurons. Acute in vitro application of human α-syn oligomers mimicked the synaptic effects observed ex vivo in PD models. CONCLUSIONS: We suggest that striatal cholinergic dysfunction, induced by a direct interaction between α-syn and GluN2D-expressing N-methyl-D-aspartate receptors, represents a precocious biological marker of the disease.
BACKGROUND: Advanced Parkinson's disease (PD) is characterized by massive degeneration of nigral dopaminergic neurons, dramatic motor and cognitive alterations, and presence of nigral Lewy bodies, whose main constituent is α-synuclein (α-syn). However, the synaptic mechanisms underlying behavioral and motor effects induced by early selective overexpression of nigral α-syn are still a matter of debate. METHODS: We performed behavioral, molecular, and immunohistochemical analyses in two transgenic models of PD, mice transgenic for truncated human α-synuclein 1-120 and rats injected with the adeno-associated viral vector carrying wild-type human α-synuclein. We also investigated striatal synaptic plasticity by electrophysiological recordings from spiny projection neurons and cholinergic interneurons. RESULTS: We found that overexpression of truncated or wild-type human α-syn causes partial reduction of striatal dopamine levels and selectively blocks the induction of long-term potentiation in striatal cholinergic interneurons, producing early memory and motor alterations. These effects were dependent on α-syn modulation of the GluN2D-expressing N-methyl-D-aspartate receptors in cholinergic interneurons. Acute in vitro application of human α-syn oligomers mimicked the synaptic effects observed ex vivo in PD models. CONCLUSIONS: We suggest that striatal cholinergic dysfunction, induced by a direct interaction between α-syn and GluN2D-expressing N-methyl-D-aspartate receptors, represents a precocious biological marker of the disease.
Authors: Dorit Trudler; Sara Sanz-Blasco; Yvonne S Eisele; Swagata Ghatak; Karthik Bodhinathan; Mohd Waseem Akhtar; William P Lynch; Juan C Piña-Crespo; Maria Talantova; Jeffery W Kelly; Stuart A Lipton Journal: J Neurosci Date: 2021-01-22 Impact factor: 6.167
Authors: J A Obeso; M Stamelou; C G Goetz; W Poewe; A E Lang; D Weintraub; D Burn; G M Halliday; E Bezard; S Przedborski; S Lehericy; D J Brooks; J C Rothwell; M Hallett; M R DeLong; C Marras; C M Tanner; G W Ross; J W Langston; C Klein; V Bonifati; J Jankovic; A M Lozano; G Deuschl; H Bergman; E Tolosa; M Rodriguez-Violante; S Fahn; R B Postuma; D Berg; K Marek; D G Standaert; D J Surmeier; C W Olanow; J H Kordower; P Calabresi; A H V Schapira; A J Stoessl Journal: Mov Disord Date: 2017-09 Impact factor: 10.338
Authors: Sharon A Swanger; Katie M Vance; Timothy M Acker; Sommer S Zimmerman; John O DiRaddo; Scott J Myers; Christoffer Bundgaard; Cara A Mosley; Samantha L Summer; David S Menaldino; Henrik S Jensen; Dennis C Liotta; Stephen F Traynelis Journal: ACS Chem Neurosci Date: 2017-11-02 Impact factor: 4.418