Hyperphosphorylation and insolubility of alpha-synuclein in transgenic mouse oligodendrocytes

(Oligodendro)glial cytoplasmic inclusions composed of α-synuclein (αSYN) characterize multiple system atrophy (MSA). Mature oligodendrocytes (OLs) do not normally express αSYN, so MSA pathology may arise from aberrant expression of αSYN in OLs. To study pathological deposition of αSYN in OLs, transgenic mice were generated in which human wild-type αSYN was driven by a proteolipid protein promoter. Transgenic αSYN was detected in OLs but no other brain cell type. At the light microscopic level, the transgenic αSYN profiles resembled glial cytoplasmic inclusions. Strikingly, the diagnostic hyperphosphorylation at S129 of αSYN was reproduced in the transgenic mice. A significant proportion of the transgenic αSYN was detergent insoluble, as in MSA patients. The histological and biochemical abnormalities were specific for the disease-relevant αSYN because control green fluorescent protein was fully soluble and evenly distributed throughout OL cell bodies and processes. Thus, ectopic expression αSYN in OLs might initiate salient features of MSA pathology.