Perampanel Inhibits α-Synuclein Transmission in Parkinson's Disease Models.
Parkinson's disease
macropinocytosis
neuronal activity
perampanel
α-synuclein
Journal
Movement disorders : official journal of the Movement Disorder Society
ISSN: 1531-8257
Titre abrégé: Mov Disord
Pays: United States
ID NLM: 8610688
Informations de publication
Date de publication:
07 2021
07 2021
Historique:
revised:
15
02
2021
received:
09
09
2020
accepted:
22
02
2021
pubmed:
5
4
2021
medline:
30
7
2021
entrez:
4
4
2021
Statut:
ppublish
Résumé
The intercellular transmission of pathogenic proteins plays a key role in the clinicopathological progression of neurodegenerative diseases. Previous studies have demonstrated that this uptake and release process is regulated by neuronal activity. The objective of this study was to examine the effect of perampanel, an antiepileptic drug, on α-synuclein transmission in cultured cells and mouse models of Parkinson's disease. Mouse primary hippocampal neurons were transduced with α-synuclein preformed fibrils to examine the effect of perampanel on the development of α-synuclein pathology and its mechanisms of action. An α-synuclein preformed fibril-injected mouse model was used to validate the effect of oral administration of perampanel on the α-synuclein pathology in vivo. Perampanel inhibited the development of α-synuclein pathology in mouse hippocampal neurons transduced with α-synuclein preformed fibrils. Interestingly, perampanel blocked the neuronal uptake of α-synuclein preformed fibrils by inhibiting macropinocytosis in a neuronal activity-dependent manner. We confirmed that oral administration of perampanel ameliorated the development of α-synuclein pathology in wild-type mice inoculated with α-synuclein preformed fibrils. Modulation of neuronal activity could be a promising therapeutic target for Parkinson's disease, and perampanel could be a novel disease-modifying drug for Parkinson's disease. © 2021 International Parkinson and Movement Disorder Society.
Sections du résumé
BACKGROUND
The intercellular transmission of pathogenic proteins plays a key role in the clinicopathological progression of neurodegenerative diseases. Previous studies have demonstrated that this uptake and release process is regulated by neuronal activity.
OBJECTIVE
The objective of this study was to examine the effect of perampanel, an antiepileptic drug, on α-synuclein transmission in cultured cells and mouse models of Parkinson's disease.
METHODS
Mouse primary hippocampal neurons were transduced with α-synuclein preformed fibrils to examine the effect of perampanel on the development of α-synuclein pathology and its mechanisms of action. An α-synuclein preformed fibril-injected mouse model was used to validate the effect of oral administration of perampanel on the α-synuclein pathology in vivo.
RESULTS
Perampanel inhibited the development of α-synuclein pathology in mouse hippocampal neurons transduced with α-synuclein preformed fibrils. Interestingly, perampanel blocked the neuronal uptake of α-synuclein preformed fibrils by inhibiting macropinocytosis in a neuronal activity-dependent manner. We confirmed that oral administration of perampanel ameliorated the development of α-synuclein pathology in wild-type mice inoculated with α-synuclein preformed fibrils.
CONCLUSION
Modulation of neuronal activity could be a promising therapeutic target for Parkinson's disease, and perampanel could be a novel disease-modifying drug for Parkinson's disease. © 2021 International Parkinson and Movement Disorder Society.
Substances chimiques
Nitriles
0
Pyridones
0
alpha-Synuclein
0
perampanel
H821664NPK
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1554-1564Commentaires et corrections
Type : CommentIn
Type : CommentIn
Informations de copyright
© 2021 International Parkinson and Movement Disorder Society.
Références
Braak H, Del Tredici K, Rüb U, de Vos RA, Jansen Steur EN, Braak E. Staging of brain pathology related to sporadic Parkinson's disease. Neurobiol Aging 2003;24:197-211.
Olanow CW, Prusiner SB. Is Parkinson's disease a prion disorder? Proc Natl Acad Sci 2009;106:12571-12572.
Lee SJ, Desplats P, Lee HJ, Spencer B, Masliah E. Cell-to-cell transmission of α-synuclein aggregates. Methods Mol Biol 2012;849:347-359.
Luk KC, Kehm V, Carroll J, et al. Pathological α-synuclein transmission initiates Parkinson-like neurodegeneration in nontransgenic mice. Science 2012;338:949-953.
Masuda-Suzukake M, Nonaka T, Hosokawa M, et al. Prion-like spreading of pathological α-synuclein in brain. Brain 2013;136:1128-1138.
Guo JL, Lee VM. Cell-to-cell transmission of pathogenic proteins in neurodegenerative diseases. Nat Med 2014;20:130-138.
Dehay B, Vila M, Bezard E, Brundin P, Kordower JH. Alpha-synuclein propagation: new insights from animal models. Mov Disord 2016;31:161-168.
Tyson T, Steiner JA, Brundin P. Sorting out release, uptake and processing of alpha-synuclein during prion-like spread of pathology. J Neurochem 2016;139:275-289.
Angot E, Brundin P. Dissecting the potential molecular mechanisms underlying alpha-synuclein cell-to-cell transfer in Parkinson's disease. Parkinsonism Relat Disord 2009;15:S143-S147.
Volpicelli-Daley LA, Luk KC, Patel TP, et al. Exogenous α-synuclein fibrils induce Lewy body pathology leading to synaptic dysfunction and neuron death. Neuron 2011;72:57-71.
Freundt EC, Maynard N, Clancy EK, et al. Neuron-to-neuron transmission of α-synuclein fibrils through axonal transport. Ann Neurol 2012;72:517-524.
Borchelt DR, Koliatsos VE, Guarnieri M, Pardo CA, Sisodia SS, Price DL. Rapid anterograde axonal transport of the cellular prion glycoprotein in the peripheral and central nervous systems. J Biol Chem 1994;269:14711-14714.
Cohen FE, Pan KM, Huang Z, Baldwin M, Fletterick RJ, Prusiner SB. Structural clues to prion replication. Science 1994;264:530-531.
Moya KL, Hässig R, Créminon C, Laffont I, Di Giamberardino L. Enhanced detection and retrograde axonal transport of PrPc in peripheral nerve. J Neurochem 2004;88:155-160.
Jucker M, Walker LC. Self-propagation of pathogenic protein aggregates in neurodegenerative diseases. Nature 2013;501:45-51.
Rey NL, Steiner JA, Maroof N, et al. Widespread transneuronal propagation of α-synucleinopathy triggered in olfactory bulb mimics prodromal Parkinson's disease. J Exp Med 2016;213:1759-1778.
Yamada K, Iwatsubo T. Extracellular α-synuclein levels are regulated by neuronal activity. Mol Neurodegener 2018;13:9.
Bero AW, Yan P, Roh JH, et al. Neuronal activity regulates the regional vulnerability to amyloid-β deposition. Nat Neurosci 2011;14:750-756.
Wu JW, Hussaini SA, Bastille IM, et al. Neuronal activity enhances tau propagation and tau pathology in vivo. Nat Neurosci 2016;19:1085-1092.
Holth JK, Fritschi SK, Wang C, et al. The sleep-wake cycle regulates brain interstitial fluid tau in mice and CSF tau in humans. Science 2019;363:880-884.
Hanada T, Hashizume Y, Tokuhara N, et al. Perampanel: a novel, orally active, noncompetitive AMPA-receptor antagonist that reduces seizure activity in rodent models of epilepsy. Epilepsia 2011;52:1331-1340.
Ceolin L, Bortolotto ZA, Bannister N, Collingridge GL, Lodge D, Volianskis A. A novel anti-epileptic agent, perampanel, selectively inhibits AMPA receptor-mediated synaptic transmission in the hippocampus. Neurochem Int 2012;61:517-522.
Chen CY, Matt L, Hell JW, Rogawski MA. Perampanel inhibition of AMPA receptor currents in cultured hippocampal neurons. PLoS One 2014;9:e108021.
Fukushima K, Hatanaka K, Sagane K, Ido K. Inhibitory effect of anti-seizure medications on ionotropic glutamate receptors: special focus on AMPA receptor subunits. Epilepsy Res 2020;167:106452.
Barygin OI. Inhibition of calcium-permeable and calcium-impermeable AMPA receptors by perampanel in rat brain neurons. Neurosci Lett 2016;633:146-151.
Yang YC, Wang GH, Chuang AY, Hsueh SW. Perampanel reduces paroxysmal depolarizing shift and inhibitory synaptic input in excitatory neurons to inhibit epileptic network oscillations. Br J Pharmacol 2020;177:5177-5194.
Uemura N, Yagi H, Uemura MT, Hatanaka Y, Yamakado H, Takahashi R. Inoculation of α-synuclein preformed fibrils into the mouse gastrointestinal tract induces Lewy body-like aggregates in the brainstem via the vagus nerve. Mol Neurodegener 2018;13:21.
Uemura N, Uemura MT, Lo A, et al. Slow progressive accumulation of oligodendroglial alpha-synuclein (α-syn) pathology in synthetic α-syn fibril-induced mouse models of synucleinopathy. J Neuropathol Exp Neurol 2019;78:877-890.
Uemura N, Ueda J, Yoshihara T, et al. α-Synuclein spread from olfactory bulb causes hyposmia, anxiety, and memory loss in BAC-SNCA mice. Mov Disord 2021. https://doi.org/10.1002/mds.28512
Akamatsu M, Yamashita T, Hirose N, Teramoto S, Kwak S. The AMPA receptor antagonist perampanel robustly rescues amyotrophic lateral sclerosis (ALS) pathology in sporadic ALS model mice. Sci Rep 2016;6:28649.
Sugiyama K, Aida T, Nomura M, Takayanagi R, Zeilhofer HU, Tanaka K. Calpain-dependent degradation of nucleoporins contributes to motor neuron death in a mouse model of chronic excitotoxicity. J Neurosci 2017;37:8830-8844.
Taguchi T, Ikuno M, Hondo M, et al. α-Synuclein BAC transgenic mice exhibit RBD-like behaviour and hyposmia: a prodromal Parkinson's disease model. Brain 2020;143:249-265.
Uemura N, Koike M, Ansai S, et al. Viable neuronopathic Gaucher disease model in Medaka (Oryzias latipes) displays axonal accumulation of alpha-synuclein. PLoS Genet 2015;11:e1005065.
Fujiwara H, Hasegawa M, Dohmae N, et al. Alpha-synuclein is phosphorylated in synucleinopathy lesions. Nat Cell Biol 2002;4:160-164.
Miksa M, Komura H, Wu R, Shah KG, Wang P. A novel method to determine the engulfment of apoptotic cells by macrophages using pHrodo succinimidyl ester. J Immunol Methods 2009;342:71-77.
Mao X, Ou MT, Karuppagounder SS, et al. Pathological α-synuclein transmission initiated by binding lymphocyte-activation gene 3. Science 2016;353(6307):30.
Loria F, Vargas JY, Bousset L, et al. α-Synuclein transfer between neurons and astrocytes indicates that astrocytes play a role in degradation rather than in spreading. Acta Neuropathol 2017;134:789-808.
Holmes BB, DeVos SL, Kfoury N, et al. Heparan sulfate proteoglycans mediate internalization and propagation of specific proteopathic seeds. Proc Natl Acad Sci 2013;110:E3138-E3147.
Münch C, O’Brien J, Bertolotti A. Prion-like propagation of mutant superoxide dismutase-1 misfolding in neuronal cells. Proc Natl Acad Sci 2011;108:3548-3553.
Zeineddine R, Pundavela JF, Corcoran L, et al. SOD1 protein aggregates stimulate macropinocytosis in neurons to facilitate their propagation. Mol Neurodegener 2015;10:57.
Gold S, Monaghan P, Mertens P, Jackson T. A clathrin independent macropinocytosis-like entry mechanism used by bluetongue virus-1 during infection of BHK cells. PLoS One 2010;5:e11360.
West MA, Bretscher MS, Watts C. Distinct endocytotic pathways in epidermal growth factor-stimulated human carcinoma A431 cells. J Cell Biol 1989;109:2731-2739.
Doyle MW, Andresen MC. Reliability of monosynaptic sensory transmission in brain stem neurons in vitro. J Neurophysiol 2001;85:2213-2223.
Uemura N, Yagi H, Uemura MT, Yamakado H, Takahashi R. Limited spread of pathology within the brainstem of α-synuclein BAC transgenic mice inoculated with preformed fibrils into the gastrointestinal tract. Neurosci Lett 2020;716:134651.
Rey NL, Petit GH, Bousset L, Melki R, Brundin P. Transfer of human α-synuclein from the olfactory bulb to interconnected brain regions in mice. Acta Neuropathol 2013;126:555-573.
Okuzumi A, Kurosawa M, Hatano T, et al. Rapid dissemination of alpha-synuclein seeds through neural circuits in an in-vivo prion-like seeding experiment. Acta Neuropathol Commun 2018;6:96.
Eggert K, Squillacote D, Barone P, et al. Safety and efficacy of perampanel in advanced Parkinson's disease: a randomized, placebo-controlled study. Mov Disord 2010;25:896-905.
Lattanzi S, Grillo E, Brigo F, Silvestrini M. Efficacy and safety of perampanel in Parkinson's disease. A systematic review with meta-analysis. J Neurol 2018;265:733-740.