Anle138b modulates α-synuclein oligomerization and prevents motor decline and neurodegeneration in a mouse model of multiple system atrophy.
Animals
Benzodioxoles
/ pharmacology
Disease Models, Animal
Mice, Transgenic
Movement Disorders
/ pathology
Multiple System Atrophy
/ drug therapy
Nerve Degeneration
/ drug therapy
Neuroglia
/ metabolism
Neurons
/ drug effects
Oligodendroglia
/ drug effects
Pyrazoles
/ pharmacology
alpha-Synuclein
/ drug effects
anle138b
movement disorders
multiple system atrophy
neurodegeneration
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:
02 2019
02 2019
Historique:
received:
24
05
2018
revised:
23
10
2018
accepted:
24
10
2018
pubmed:
20
11
2018
medline:
3
1
2020
entrez:
20
11
2018
Statut:
ppublish
Résumé
MSA is a fatal neurodegenerative disease characterized by autonomic failure and severe motor impairment. Its main pathological hallmark is the accumulation of α-synuclein in oligodendrocytes, leading to glial and neuronal dysfunction and neurodegeneration. These features are recapitulated in the PLP-hαSyn mouse model expressing human α-synuclein in oligodendrocytes. At present, there is no effective disease-modifying therapy. Previous experiments have shown that the aggregation inhibitor, anle138b, reduces neurodegeneration and behavioral deficits in mouse models of other proteinopathies. To test the therapeutic potential of anle138b in a mouse model of MSA. Two-month-old PLP-hαSyn mice were fed over a period of 4 months with pellets containing anle138b at two different doses (0.6 and 2 g/kg) and compared to healthy controls and PLP-hαSyn mice fed with placebo pellets. At the end of the treatment, behavioral and histological analyses were performed. We observed a reversal of motor function to healthy control levels when PLP-hαSyn mice were treated with both doses of anle138b. Histological and molecular analyses showed a significant reduction in α-synuclein oligomers and glial cytoplasmic inclusions in animals fed with anle138b compared to nontreated mice. These animals also present preservation of dopaminergic neurons and reduction in microglial activation in SN correlating with the α-synuclein reduction observed. Anle138b reduces α-synuclein accumulation in PLP-hαSyn mice, leading to neuroprotection, reduction of microglial activation, and preservation of motor function supporting the use of anle138b in a future clinical trial for MSA. © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.
Sections du résumé
BACKGROUND
MSA is a fatal neurodegenerative disease characterized by autonomic failure and severe motor impairment. Its main pathological hallmark is the accumulation of α-synuclein in oligodendrocytes, leading to glial and neuronal dysfunction and neurodegeneration. These features are recapitulated in the PLP-hαSyn mouse model expressing human α-synuclein in oligodendrocytes. At present, there is no effective disease-modifying therapy. Previous experiments have shown that the aggregation inhibitor, anle138b, reduces neurodegeneration and behavioral deficits in mouse models of other proteinopathies.
OBJECTIVES
To test the therapeutic potential of anle138b in a mouse model of MSA.
METHODS
Two-month-old PLP-hαSyn mice were fed over a period of 4 months with pellets containing anle138b at two different doses (0.6 and 2 g/kg) and compared to healthy controls and PLP-hαSyn mice fed with placebo pellets. At the end of the treatment, behavioral and histological analyses were performed.
RESULTS
We observed a reversal of motor function to healthy control levels when PLP-hαSyn mice were treated with both doses of anle138b. Histological and molecular analyses showed a significant reduction in α-synuclein oligomers and glial cytoplasmic inclusions in animals fed with anle138b compared to nontreated mice. These animals also present preservation of dopaminergic neurons and reduction in microglial activation in SN correlating with the α-synuclein reduction observed.
CONCLUSIONS
Anle138b reduces α-synuclein accumulation in PLP-hαSyn mice, leading to neuroprotection, reduction of microglial activation, and preservation of motor function supporting the use of anle138b in a future clinical trial for MSA. © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.
Identifiants
pubmed: 30452793
doi: 10.1002/mds.27562
pmc: PMC6492169
doi:
Substances chimiques
3-(1,3-benzodioxol-5-yl)-5-(3-bromophenyl)-1H-pyrazole
0
Benzodioxoles
0
Pyrazoles
0
alpha-Synuclein
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
255-263Subventions
Organisme : Austrian Science Fund FWF
ID : I 2102
Pays : Austria
Organisme : Austrian Science Fund (FWF)
ID : I2102
Pays : International
Organisme : Austrian Science Fund (FWF)
ID : F4414
Pays : International
Organisme : FP7 Health
ID : 602646
Pays : International
Informations de copyright
© 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.
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