Hyperphosphorylation and insolubility of α-synuclein in transgenic mouse oligodendrocytes

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