A novel mouse model for investigating α-synuclein aggregates in oligodendrocytes: implications for the glial cytoplasmic inclusions in multiple system atrophy

The aggregated alpha-synuclein (alpha syn) in oligodendrocytes (OLGs) is one of the pathological hallmarks in multiple system atrophy (MSA). We have previously reported that alpha syn accumulates not only in neurons but also in OLGs long after the administration of alpha syn preformed fibrils (PFFs) in mice. However, detailed spatial and temporal analysis of oligodendroglial alpha syn aggregates was technically difficult due to the background neuronal alpha syn aggregates. The aim of this study is to create a novel mouse that easily enables sensitive and specific detection of alpha syn aggregates in OLGs and the comparable analysis of the cellular tropism of alpha syn aggregates in MSA brains. To this end, we generated transgenic (Tg) mice expressing human alpha syn-green fluorescent protein (GFP) fusion proteins in OLGs under the control of the 2', 3'-cyclic nucleotide 3'-phosphodiesterase (CNP) promoter (CNP-SNCAGFP Tg mice). Injection of alpha syn PFFs in these mice induced distinct GFP-positive aggregates in the processes of OLGs as early as one month post-inoculation (mpi), and their number and size increased in a centripetal manner. Moreover, MSA-brain homogenates (BH) induced significantly more oligodendroglial alpha syn aggregates than neuronal alpha syn aggregates compared to DLB-BH in CNP-SNCAGFP Tg mice, suggestive of their potential tropism of alpha syn seeds for OLGs. In conclusion, CNP-SNCAGFP Tg mice are useful for studying the development and tropism of alpha syn aggregates in OLGs and could contribute to the development of therapeutics targeting alpha syn aggregates in OLGs.