Anle138b partly ameliorates motor deficits despite failure of neuroprotection in a model of advanced multiple system atrophy
The neurodegenerative disorder multiple system atrophy (MSA) is characterized by autonomic failure, cerebellar ataxia and parkinsonism in any combination associated with predominantly oligodendroglial α-synuclein (α-syn) aggregates (glial cytoplasmic inclusions=GCIs). To date, there is no effective...
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doaj-e65416851a704aa0902ca1d733644db32020-11-25T00:15:27ZengFrontiers Media S.A.Frontiers in Neuroscience1662-453X2016-03-011010.3389/fnins.2016.00099186431Anle138b partly ameliorates motor deficits despite failure of neuroprotection in a model of advanced multiple system atrophyLisa eFellner0Daniela eKuzdas-Wood1Johannes eLevin2Sergey eRyazanov3Sergey eRyazanov4Andrei eLeonov5Andrei eLeonov6Christian eGriesinger7Christian eGriesinger8Armin eGiese9Gregor K Wenning10Nadia eStefanova11Medical University of InnsbruckMedical University of InnsbruckKlinikum der Ludwig-Maximilians-Universität MünchenMax Planck Institute for Biophysical ChemistryDFG Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB)Max Planck Institute for Biophysical ChemistryDFG Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB)Max Planck Institute for Biophysical ChemistryDFG Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB)Ludwig-Maximilian-Universität MünchenMedical University of InnsbruckMedical University of InnsbruckThe neurodegenerative disorder multiple system atrophy (MSA) is characterized by autonomic failure, cerebellar ataxia and parkinsonism in any combination associated with predominantly oligodendroglial α-synuclein (α-syn) aggregates (glial cytoplasmic inclusions=GCIs). To date, there is no effective disease modifying therapy. Previous experiments have shown that the aggregation inhibitor anle138b reduces neurodegeneration, as well as behavioral deficits in both transgenic and toxin mouse models of Parkinson’s disease (PD). Here we analyzed whether anle138b improves motor skills and reduces neuronal loss, as well as oligodendroglial α-syn aggregation in the PLP-α-syn transgenic mouse challenged with the mitochondrial toxin 3-nitropropionic acid (3-NP) to model full-blown MSA. Following one month of treatment with anle138b, MSA mice showed signs of motor improvement affecting stride length, but not pole, grip strength and beam test performance. Loss of dopaminergic nigral neurons and Purkinje cells was not attenuated and GCI density remained unchanged. These data suggest that the pathology in transgenic PLP-α-syn mice receiving 3-NP might be too advanced to detect significant effects of anle138b treatment on neuronal loss and intracytoplasmic α-syn inclusion bodies. However, the partial motor amelioration may indicate potential efficacy of anle138b treatment that may be mediated by its actions on α-syn oligomers or may reflect improvement of neuronal dysfunction in neural at risk populations. Further studies are required to address the efficacy of anle138b in transgenic α-syn models of early-stage MSA and in the absence of additional toxin application.http://journal.frontiersin.org/Journal/10.3389/fnins.2016.00099/fullMultiple System Atrophyα-SynucleinGlial cytoplasmic inclusions3- Nitropropionic acidAnle138b |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Lisa eFellner Daniela eKuzdas-Wood Johannes eLevin Sergey eRyazanov Sergey eRyazanov Andrei eLeonov Andrei eLeonov Christian eGriesinger Christian eGriesinger Armin eGiese Gregor K Wenning Nadia eStefanova |
spellingShingle |
Lisa eFellner Daniela eKuzdas-Wood Johannes eLevin Sergey eRyazanov Sergey eRyazanov Andrei eLeonov Andrei eLeonov Christian eGriesinger Christian eGriesinger Armin eGiese Gregor K Wenning Nadia eStefanova Anle138b partly ameliorates motor deficits despite failure of neuroprotection in a model of advanced multiple system atrophy Frontiers in Neuroscience Multiple System Atrophy α-Synuclein Glial cytoplasmic inclusions 3- Nitropropionic acid Anle138b |
author_facet |
Lisa eFellner Daniela eKuzdas-Wood Johannes eLevin Sergey eRyazanov Sergey eRyazanov Andrei eLeonov Andrei eLeonov Christian eGriesinger Christian eGriesinger Armin eGiese Gregor K Wenning Nadia eStefanova |
author_sort |
Lisa eFellner |
title |
Anle138b partly ameliorates motor deficits despite failure of neuroprotection in a model of advanced multiple system atrophy |
title_short |
Anle138b partly ameliorates motor deficits despite failure of neuroprotection in a model of advanced multiple system atrophy |
title_full |
Anle138b partly ameliorates motor deficits despite failure of neuroprotection in a model of advanced multiple system atrophy |
title_fullStr |
Anle138b partly ameliorates motor deficits despite failure of neuroprotection in a model of advanced multiple system atrophy |
title_full_unstemmed |
Anle138b partly ameliorates motor deficits despite failure of neuroprotection in a model of advanced multiple system atrophy |
title_sort |
anle138b partly ameliorates motor deficits despite failure of neuroprotection in a model of advanced multiple system atrophy |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Neuroscience |
issn |
1662-453X |
publishDate |
2016-03-01 |
description |
The neurodegenerative disorder multiple system atrophy (MSA) is characterized by autonomic failure, cerebellar ataxia and parkinsonism in any combination associated with predominantly oligodendroglial α-synuclein (α-syn) aggregates (glial cytoplasmic inclusions=GCIs). To date, there is no effective disease modifying therapy. Previous experiments have shown that the aggregation inhibitor anle138b reduces neurodegeneration, as well as behavioral deficits in both transgenic and toxin mouse models of Parkinson’s disease (PD). Here we analyzed whether anle138b improves motor skills and reduces neuronal loss, as well as oligodendroglial α-syn aggregation in the PLP-α-syn transgenic mouse challenged with the mitochondrial toxin 3-nitropropionic acid (3-NP) to model full-blown MSA. Following one month of treatment with anle138b, MSA mice showed signs of motor improvement affecting stride length, but not pole, grip strength and beam test performance. Loss of dopaminergic nigral neurons and Purkinje cells was not attenuated and GCI density remained unchanged. These data suggest that the pathology in transgenic PLP-α-syn mice receiving 3-NP might be too advanced to detect significant effects of anle138b treatment on neuronal loss and intracytoplasmic α-syn inclusion bodies. However, the partial motor amelioration may indicate potential efficacy of anle138b treatment that may be mediated by its actions on α-syn oligomers or may reflect improvement of neuronal dysfunction in neural at risk populations. Further studies are required to address the efficacy of anle138b in transgenic α-syn models of early-stage MSA and in the absence of additional toxin application. |
topic |
Multiple System Atrophy α-Synuclein Glial cytoplasmic inclusions 3- Nitropropionic acid Anle138b |
url |
http://journal.frontiersin.org/Journal/10.3389/fnins.2016.00099/full |
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