Miguel Lopez-Cuina1,2, Paul A Guerin1,2, Marie-Hélène Canron1,2, Anna Delamarre1,2, Benjamin Dehay1,2, Erwan Bezard1,2, Wassilios G Meissner1,2,3,4, Pierre-Olivier Fernagut1,2,5,6. 1. Univ. de Bordeaux, Institut des Maladies Neurodégénératives, Bordeaux, France. 2. CNRS, Institut des Maladies Neurodégénératives, Bordeaux, France. 3. Service de Neurologie, CRMR Atrophie Multisystématisée, CHU Bordeaux, Bordeaux, France. 4. Dept. Medicine, University of Otago, Christchurch, New Zealand, and New Zealand Brain Research Institute, Christchurch, New Zealand. 5. Laboratoire de Neurosciences Expérimentales et Cliniques, Université de Poitiers, Poitiers, France. 6. INSERM, Laboratoire de Neurosciences Expérimentales et Cliniques, Poitiers, France.
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.
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.