Mouse model of multiple system atrophy α-synuclein expression in oligodendrocytes causes glial and neuronal degeneration

Transgenic (Tg) mice overexpressing human wild-type alpha-synuclein in oligodendrocytes under the control of the 2,' 3'-cyclic nucleotide X-phosphodiesterase (CNP) promoter are shown here to recapitulate features of multiple system atrophy (MSA), including the accumulation of filamentous human alpha-synuclein aggregates in oligodendrocytes linked to their degeneration and autophagocytosis of myelin. Significantly, endogenous mouse (x-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 alpha-synuclein in oligodendrocytes of mice results in MSA-like degeneration in the CNS and that a-synuclein inclusions in oligodendrocytes participate in the degeneration of neurons in MSA.