title: Reducing C-terminal truncation mitigates synucleinopathy and neurodegeneration in a transgenic model of multiple system atrophy.
abstract: Multiple system atrophy (MSA) is a sporadic orphan neurodegenerative disorder. No treatment is currently available to slow down the aggressive neurodegenerative process, and patients die within a few years after disease onset. The cytopathological hallmark of MSA is the accumulation of alpha-synuclein (α-syn) aggregates in affected oligodendrocytes. Several studies point to α-syn oligomerization and aggregation as a mediator of neurotoxicity in synucleinopathies including MSA. C-terminal truncation by the inflammatory protease caspase-1 has recently been implicated in the mechanisms that promote aggregation of α-syn in vitro and in neuronal cell models of α-syn toxicity. We present here an in vivo proof of concept of the ability of the caspase-1 inhibitor prodrug VX-765 to mitigate α-syn pathology and to mediate neuroprotection in proteolipid protein α-syn (PLP-SYN) mice, a transgenic mouse model of MSA. PLP-SYN and age-matched wild-type mice were treated for a period of 11 wk with VX-765 or placebo. VX-765 prevented motor deficits in PLP-SYN mice compared with placebo controls. More importantly, VX-765 was able to limit the progressive toxicity of α-syn aggregation by reducing its load in the striatum of PLP-SYN mice. Not only did VX-765 reduce truncated α-syn, but it also decreased its monomeric and oligomeric forms. Finally, VX-765 showed neuroprotective effects by preserving tyrosine hydroxylase-positive neurons in the substantia nigra of PLP-SYN mice. In conclusion, our results suggest that VX-765, a drug that was well tolerated in a 6 wk-long phase II trial in patients with epilepsy, is a promising candidate to achieve disease modification in synucleinopathies by limiting α-syn accumulation.
authors.affiliation: Université de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, F-33000 Bordeaux, France; CNRS, Institut des Maladies Neurodégénératives, UMR 5293, F-33000 Bordeaux, France;
authors.forename: Fares
authors.initials: F
authors.lastname: Bassil
authors.affiliation: Université de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, F-33000 Bordeaux, France; CNRS, Institut des Maladies Neurodégénératives, UMR 5293, F-33000 Bordeaux, France;
authors.forename: Pierre-Olivier
authors.initials: PO
authors.lastname: Fernagut
authors.affiliation: Université de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, F-33000 Bordeaux, France; CNRS, Institut des Maladies Neurodégénératives, UMR 5293, F-33000 Bordeaux, France;
authors.forename: Erwan
authors.initials: E
authors.lastname: Bezard
authors.affiliation: Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Institut de Biologie et de Technologies de Saclay (iBiTec-S), Service de Pharmacologie et d'Immunoanalyse (SPI), Université Paris Saclay, F-91191 Gif sur Yvette, France;
authors.forename: Alain
authors.initials: A
authors.lastname: Pruvost
authors.affiliation: INSERM, Neurocentre Magendie, U1215, Physiopathologie de la Plasticité Neuronale, F-33000 Bordeaux, France;
authors.forename: Thierry
authors.initials: T
authors.lastname: Leste-Lasserre
authors.affiliation: Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202;
authors.forename: Quyen Q
authors.initials: QQ
authors.lastname: Hoang
authors.affiliation: Rosenstiel Basic Medical Sciences Research Center, Brandeis University, Waltham, MA 02465;
authors.forename: Dagmar
authors.initials: D
authors.lastname: Ringe
authors.affiliation: Rosenstiel Basic Medical Sciences Research Center, Brandeis University, Waltham, MA 02465; Appel Alzheimer's Disease Research Institute, Weill Cornell Medical College, New York, NY 10021; wassilios.meissner@chu-bordeaux.fr gpetsko@med.cornell.edu.
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Petsko
authors.affiliation: Université de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, F-33000 Bordeaux, France; CNRS, Institut des Maladies Neurodégénératives, UMR 5293, F-33000 Bordeaux, France; Centre de Référence Maladie Rare Atrophie Multisystématisée, Service de Neurologie, Hôpital Pellegrin, Centre Hospitalier Universitaire de Bordeaux, F-33076 Bordeaux, France wassilios.meissner@chu-bordeaux.fr gpetsko@med.cornell.edu.
authors.forename: Wassilios G
authors.initials: WG
authors.lastname: Meissner
mesh_terms: D000818:Animals; D020170:Caspase 1 / Q000235:genetics* / Q000378:metabolism; D002986:Clinical Trials as Topic; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D004151:Dipeptides / Q000494:pharmacology*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D019578:Multiple System Atrophy / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009836:Oligodendroglia / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D066329:Protein Aggregates / Q000187:drug effects / Q000235:genetics; D059748:Proteolysis; D015398:Signal Transduction; D013378:Substantia Nigra / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics / Q000378:metabolism; D051844:alpha-Synuclein / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D062366:para-Aminobenzoates / Q000494:pharmacology*
chemical_list: D004151:Dipeptides; D066329:Protein Aggregates; C497605:Snca protein, mouse; D051844:alpha-Synuclein; D062366:para-Aminobenzoates; C520022:belnacasan; D014446:Tyrosine 3-Monooxygenase; D020170:Caspase 1
keywords: alpha-synuclein; caspase-1; multiple system atrophy; truncation