We also analyzed gene expression data from post-mortem human brains which had been scored by neuropathologists for their Braak stage 50. Differential expression was calculated between brains with Braak scores of zero (controls) and brains with Braak scores of 1—2, 3—4 and 5—6. At the latter stages (Braak scores 3—4 and 5—6), downregulated genes were specifically expressed in dopaminergic neurons, while upregulated genes were specifically expressed in oligodendrocytes (Figure 5), as observed in the case-control studies. Moreover, Braak stage 1 and 2 are characterized by little degeneration in the substantia nigra and, consistently, we found that downregulated genes were not enriched in dopaminergic neurons at this stage. Notably, upregulated genes were already strongly enriched in oligodendrocytes at Braak Stages 1–2. These results not only support the genetic evidence indicating that oligodendrocytes may play a causal role in Parkinson’s disease, but indicate that their involvement precedes the emergence of pathological changes in the substantia nigra.
