Reducing C-terminal truncation mitigates synucleinopathy and neurodegeneration in a transgenic model of multiple system atrophy.

Fares Bassil, Pierre-Olivier Fernagut, Erwan Bezard, Alain Pruvost, Thierry Leste-Lasserre, Quyen Q. Hoang, Dagmar Ringe, Gregory A. Petsko, Wassilios G. Meissner
Proc Natl Acad Sci USA. 2016-08-01; 113(34): 9593-9598
DOI: 10.1073/pnas.1609291113

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1. Proc Natl Acad Sci U S A. 2016 Aug 23;113(34):9593-8. doi:
10.1073/pnas.1609291113. Epub 2016 Aug 1.

Reducing C-terminal truncation mitigates synucleinopathy and neurodegeneration in
a transgenic model of multiple system atrophy.

Bassil F(1), Fernagut PO(1), Bezard E(1), Pruvost A(2), Leste-Lasserre T(3),
Hoang QQ(4), Ringe D(5), Petsko GA(6), Meissner WG(7).

Author information:
(1)Université de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293,
F-33000 Bordeaux, France; CNRS, Institut des Maladies Neurodégénératives, UMR
5293, F-33000 Bordeaux, France;
(2)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;
(3)INSERM, Neurocentre Magendie, U1215, Physiopathologie de la Plasticité
Neuronale, F-33000 Bordeaux, France;
(4)Department of Biochemistry and Molecular Biology, Indiana University School of
Medicine, Indianapolis, IN 46202;
(5)Rosenstiel Basic Medical Sciences Research Center, Brandeis University,
Waltham, MA 02465;
(6)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;
.
(7)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
.

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.

DOI: 10.1073/pnas.1609291113
PMCID: PMC5003293
PMID: 27482103 [Indexed for MEDLINE]

Conflict of interest statement: The authors declare no conflict of interest.

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