Anle138b Partly Ameliorates Motor Deficits Despite Failure of Neuroprotection in a Model of Advanced Multiple System Atrophy.

Lisa Fellner,Armin Giese,Daniela Kuzdas-Wood,Gregor K Wenning,Sergey Ryazanov,Christian Griesinger,Nadia Stefanova,Johannes Levin,Andrei Leonov

doi:10.3389/fnins.2016.00099

Abstract

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 1 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.

Highlights

Multiple system atrophy (MSA) is a progressive, adult-onset neurodegenerative disorder that belongs to the spectrum of α-synucleinopathies (ASP)
As MSA is a fatal primary oligodendrogliopathy associated with GCIs and selective multisystem neurodegeneration novel therapeutic drugs that attenuate brain pathology are of great importance
In the current study we investigated for the first time the effect of the novel aggregation inhibitor anle138b on behavioral outcome, neurodegeneration and α-syn aggregates in MSA mice exposed to mitochondrial inhibition

Summary

Introduction

Multiple system atrophy (MSA) is a progressive, adult-onset neurodegenerative disorder that belongs to the spectrum of α-synucleinopathies (ASP). MSA patients present with parkinsonism, cerebellar, autonomic, and pyramidal dysfunction in any combination (Fanciulli and Wenning, 2015). Two major types of MSA are distinguished: striatonigral degeneration (SND) underlies the parkinsonian variant of MSA whereas olivopontocerebellar atrophy (OPCA) is associated with the cerebellar subtype. In MSA α-synuclein (α-syn) accumulates in oligodendrocytes (glial cytoplasmic inclusions = GCIs or Papp-Lantos bodies). Α-syn-positive inclusions may appear in neurons (Cykowski et al, 2015) as well and sometimes in astroglial cells similar to other ASP, such as Parkinson’s disease (PD) and dementia with Lewy bodies (DLB). The various inclusions appear to contribute to the neurodegeneration associated with MSA (Wenning et al, 2008). More recent evidence suggests that toxic α-syn aggregates might induce a prion-like spreading in MSA and related ASP (Angot et al, 2010; Reyes et al, 2014; Prusiner et al, 2015)

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