Viral-mediated oligodendroglial expression of α-synuclein allows replicating some of the key features of MSA. This flexible strategy can be used to investigate, in several species, how α-synuclein accumulation in selected oligodendroglial populations contributes to the pathophysiology of MSA and offers a new framework for preclinical validation of therapeutic strategies. © 2017 International Parkinson and Movement Disorder Society.

BackgroundMultiple 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.MethodsMice 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.Resultsα‐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.ConclusionsThis 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

Background Multiple system atrophy (MSA) is a sporadic adult‐onset rare neurodegenerative synucleinopathy for which counteracting central nervous system insulin resistance bears the potential of being neuroprotective. G‐protein‐(heterotrimeric guanine nucleotide‐binding protein)‐coupled receptor kinase 2 (GRK2) is emerging as a physiologically relevant inhibitor of insulin signaling. Objectives We tested whether lowering brain GRK2 abundance may reverse insulin‐resistance. Methods We lowered brain GRK2 abundance through viral‐mediated delivery of a GRK2‐specific miRNA and quantified the reversion of a developing or an established insulin‐resistant phenotype using the transgenic PLP‐SYN mouse model of MSA. Results Viral vector delivery of a GRK2 miRNA demonstrated a neuroprotective capacity when administered (1) in utero intracerebroventricularly in developing PLP‐SYN mice and (2) intrastriatally in adult PLP‐SYN mice. Decreased striatal GRK2 levels correlated in both designs with neuroprotection of the substantia nigra dopamine neurons, reduction in high‐molecular‐weight species of α‐synuclein, and reduced insulin resistance. Conclusions These data support GRK2 as a potential therapeutic target in MSA. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.