Mouse Model of Multiple System Atrophy α-Synuclein Expression in Oligodendrocytes Causes Glial and Neuronal Degeneration

SummaryTransgenic (Tg) mice overexpressing human wild-type α-synuclein in oligodendrocytes under the control of the 2,′ 3′-cyclic nucleotide 3′-phosphodiesterase (CNP) promoter are shown here to recapitulate features of multiple system atrophy (MSA), including the accumulation of filamentous human α-synuclein aggregates in oligodendrocytes linked to their degeneration and autophagocytosis of myelin. Significantly, endogenous mouse α-synuclein also accumulated in normal and degenerating axons and axon terminals in association with oligodendroglia and neuron loss and slowly progressive motor impairments. Our studies demonstrate that overexpression of α-synuclein in oligodendrocytes of mice results in MSA-like degeneration in the CNS and that α-synuclein inclusions in oligodendrocytes participate in the degeneration of neurons in MSA