Behavioral Characterization of a Transgenic Mouse Model of Multiple System Atrophy

Multiple system atrophy (MSA) is a rare neurodegenerative disorder of unknown etiology, characterized by autonomic dysfunction, parkinsonism, and cerebellar syndrome. α-synuclein (αSyn) is the main component of glial cytoplasmic inclusions (GCIs), which are one of the histopathological hallmarks of the disease. To better understand MSA pathology and test potential disease-modifying interventions, several pre-clinical models have been developed. Although many of them replicate certain neuropathological and functional features of MSA, none fully recapitulates the human disease. In this study, we characterized the behavioral phenotype of a new transgenic mouse model overexpressing murine wild-type αSyn under the control of the oligodendrocytic myelin basic protein (MBP) promoter, named the MmMBP-Mmα-Syn mouse model. Limited signs of motor impairment were observed in the transgenic model, consistent with the absence of detectable αSyn fibrillar aggregates resembling GCIs in these mice. The behavioral tests were also performed on MmMBP-Mmα-Syn mice following injection of murine αSyn pre-formed fibrils (mPFFs) in the pons, with the intention of seeding αSyn aggregation and subsequent propagation of the pathology. The combined model also displayed minimal alterations in anxiety-related behaviors and motor performance. These findings suggest that visible motor pathology-related alterations may only develop at a later age or a longer post-injection period.