Possible pathological a-Syn-spreading and accumulation mechanism leading to neurodegeneration. (A) Healthy neuron, oligodendrocyte, microglia and astrocyte, p25a mainly located in the myelinating oligodendroglial processes, monomeric a-Syn present in presynaptic nerve terminals. (B) Relocalisation of p25a from the processes to the soma, inclusion formation and swelling of the oligodendroglial soma. (C) Oligomeric a-Syn accumulation in the oligodendroglial cytoplasm, the exact source of a-Syn remains to be investigated. Possible hypotheses include exocytosed a-Syn from neurons and uptake into oligodendrocytes by cell-to-cell propagation or upregulation of a- Syn expression in oligodendrocytes themselves. In addition, axonal a-Syn may be taken up by the dysfunctional oligodendroglial myelin compartment. (D) a-Syn aggregates form insoluble half-moon shaped GCIs characteristic for the disease. (E) Disruption of trophic support (e.g. GDNF), mitochondrial failure, increased production of reactive oxygen species (ROS) and proteasomal dysfunction occur. (F) Oligodendrocytes suffer from severe distress and will eventually degrade. (G) Activation of micro/astroglial cells by cytokines released from the damaged oligodendrocytes, proposed secondary neuronal loss potentially due to lack of trophic support, ROS production, proteasomal failure and pro-inflammatory environment. Reproduced with the courtesy of Elsevier.