Volume 35, Issue 7 p. 1163-1172
Research Article

Nilotinib Fails to Prevent Synucleinopathy and Cell Loss in a Mouse Model of Multiple System Atrophy

Miguel Lopez-Cuina MD, PhD

Miguel Lopez-Cuina MD, PhD

Univ. de Bordeaux, Institut des Maladies Neurodégénératives, Bordeaux, France

CNRS, Institut des Maladies Neurodégénératives, Bordeaux, France

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Paul A. Guerin PhD

Paul A. Guerin PhD

Univ. de Bordeaux, Institut des Maladies Neurodégénératives, Bordeaux, France

CNRS, Institut des Maladies Neurodégénératives, Bordeaux, France

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Marie-Hélène Canron BS

Marie-Hélène Canron BS

Univ. de Bordeaux, Institut des Maladies Neurodégénératives, Bordeaux, France

CNRS, Institut des Maladies Neurodégénératives, Bordeaux, France

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Anna Delamarre MD

Anna Delamarre MD

Univ. de Bordeaux, Institut des Maladies Neurodégénératives, Bordeaux, France

CNRS, Institut des Maladies Neurodégénératives, Bordeaux, France

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Benjamin Dehay PhD

Benjamin Dehay PhD

Univ. de Bordeaux, Institut des Maladies Neurodégénératives, Bordeaux, France

CNRS, Institut des Maladies Neurodégénératives, Bordeaux, France

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Erwan Bezard PhD

Erwan Bezard PhD

Univ. de Bordeaux, Institut des Maladies Neurodégénératives, Bordeaux, France

CNRS, Institut des Maladies Neurodégénératives, Bordeaux, France

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Wassilios G. Meissner MD, PhD

Wassilios G. Meissner MD, PhD

Univ. de Bordeaux, Institut des Maladies Neurodégénératives, Bordeaux, France

CNRS, Institut des Maladies Neurodégénératives, Bordeaux, France

Service de Neurologie, CRMR Atrophie Multisystématisée, CHU Bordeaux, Bordeaux, France

Dept. Medicine, University of Otago, Christchurch, New Zealand, and New Zealand Brain Research Institute, Christchurch, New Zealand

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Pierre-Olivier Fernagut PhD

Corresponding Author

Pierre-Olivier Fernagut PhD

Univ. de Bordeaux, Institut des Maladies Neurodégénératives, Bordeaux, France

CNRS, Institut des Maladies Neurodégénératives, Bordeaux, France

Laboratoire de Neurosciences Expérimentales et Cliniques, Université de Poitiers, Poitiers, France

INSERM, Laboratoire de Neurosciences Expérimentales et Cliniques, Poitiers, France

Correspondence to: Pierre-Olivier Fernagut, Université de Poitiers, Laboratoire de Neurosciences Expérimentales et Cliniques, UMR_S 1084, F-86000 Poitiers, France; E-mail: [email protected]Search for more papers by this author
First published: 14 April 2020
Citations: 13
Miguel Lopez-Cuina and Paul A. Guerin are first authors. Wassilios G. Meissner and Pierre-Olivier Fernagut are senior authors.
Relevant conflicts of interest/financial disclosures: None.
Funding agencies: This work was supported by a grant from the MSA Coalition.

Abstract

Background

Multiple system atrophy (MSA) is a rare, untreatable neurodegenerative disorder characterized by accumulation of α-synuclein in oligodendroglial inclusions. As such, MSA is a synucleinopathy along with Parkinson's disease (PD) and dementia with Lewy bodies. Activation of the abelson tyrosine kinase c-Abl leads to phosphorylation of α-synuclein at tyrosine 39, thereby promoting its aggregation and subsequent neurodegeneration. The c-Abl inhibitor nilotinib used for the treatment of chronic myeloid leukemia based on data collected in preclinical models of PD might interfere with pathogenic mechanisms that are relevant to PD and dementia with Lewy bodies, which motivated its assessment in an open-label clinical trial in PD and dementia with Lewy bodies patients. The objective of this study was to assess the preclinical efficacy of nilotinib in the specific context of MSA.

Methods

Mice expressing human wild-type α-synuclein in oligodendrocytes received daily injection of nilotinib (1 or 10 mg/kg) over 12 weeks. Postmortem analysis included the assessment of c-Abl activation, α-synuclein burden, and dopaminergic neurodegeneration.

Results

α-Synuclein phosphorylated at tyrosine 39 was detected in glial cytoplasmic inclusions in MSA patients. Increased activation of c-Abl and α-synuclein phosphorylation at tyrosine 39 were found in transgenic mice. Despite significant inhibition of c-Abl and associated reduction of α-synuclein phosphorylation at tyrosine 39 by 40%, nilotinib failed to reduce α-synuclein aggregate burden (including phosphorylation at serine 129) in the striatum and cortex or to lessen neurodegeneration in the substantia nigra.

Conclusions

This preclinical study suggests that partial inhibition of c-Abl and reduction of α-synuclein phosphorylation at tyrosine 39 may not be a relevant target for MSA. © 2020 International Parkinson and Movement Disorder Society