Objective: We characterized the formation of α-synuclein pathology and development of motor phenotypes in a mouse model of multiple system atrophy overexpressing human SNCA in only oligodendrocytes on a mouse Snca knockout background.

Background: Multiple system atrophy (MSA) is primarily characterized by the formation of α-synuclein (αSyn) pathology in oligodendrocytes. However, both oligodendroglial and neuronal αSyn pathology are frequently observed in MSA patient brains. It remains unclear whether the driving cause of neurodegeneration and progressive phenotype in MSA is: i) loss of trophic support and myelination resulting from oligodendrocytic αSyn pathology formation or ii) transmission of αSyn pathology into neurons. We developed and characterized a novel mouse model to restrict αSyn pathology to oligodendrocytes.

Method: A mouse line expressing full-length human SNCA under the oligodendrocyte-enriched murine CNP promoter (M2) [1] was crossed to Snca-/- mice [2] to generate KOM2 mice expressing αSyn only in oligodendrocytes. Double homozygous KOM2 mice were aged alongside same-sex littermates and monitored for motor impairments. Upon severe motor dysfunction, brains were processed for immunohistochemistry.

Results: Development of spontaneous motor dysfunction—including tremor, impaired coordination, and freezing—was associated with the widespread formation of αSyn pathology in oligodendrocytic cells across cortical, midbrain, and cerebellar regions, particularly in white-matter-enriched regions such as the corpus callosum. Minimal neuronal αSyn was observed, indicating that oligodendrocyte-specific human SNCA expression was successful.

Conclusion: Overexpression of αSyn in oligodendrocytes is sufficient to generate oligodendroglial αSyn pathology and motor dysfunction in our model, even in the absence of neuronal αSyn expression, suggesting that neuronal αSyn pathology is not necessary to induce a MSA-like phenotype.

References: [1] Yazawa I, Giasson BI, Sasaki R, Zhang B, Joyce S, Uryu K, Trojanowski JQ, Lee VMY. Mouse model of multiple system atrophy α-synuclein expression in oligodendrocytes causes glial and neuronal degeneration. Neuron. 2005;45(6):847-859. doi:10.1016/j.neuron.2005.01.032

[2] Abeliovich A, Schmitz Y, Fariñas I, Choi-Lundberg D, Ho WH, Castillo PE, Shinsky N, Verdugo JM, Armanini M, Ryan A, Hynes M, Phillips H, Sulzer D, Rosenthal A. Mice lacking alpha-synuclein display functional deficits in the nigrostriatal dopamine system. Neuron. 2000;25(1):239-252. doi:10.1016/s0896-6273(00)80886-7

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MDS Abstracts - https://www.mdsabstracts.org/abstract/oligodendrocyte-specific-%ce%b1-synuclein-pathology-is-linked-to-severe-motor-phenotype-in-a-novel-mouse-model-of-multiple-system-atrophy/