Testing an inverse link between limbic alpha-synucleinopathy and myelin markers in mice and humans

In Lewy body disease, alpha-synucleinopathic inclusions tend to develop in brain regions that extend long, thin, and unmyelinated projection fibers, but it is not known if this selective vulnerability is caused by poor myelination status. Our objective was to investigate this link in the limbic forebrain. First, we observed that levels of insoluble, hyperphosphorylated alpha-synuclein correlated inversely with the myelin marker proteolipid protein (20 kDa isoform) in the amygdala of men (but not women) with Lewy body disease. Second, select oligodendrocytic markers were mildly suppressed in the amygdala of men with Lewy body disease. Third, preformed fibrils (PFFs) of alpha-synuclein tended to induce greater pathology in gray matter, even when infused into murine brain regions penetrated by myelinated fiber bundles. Given these correlative patterns, we tested the hypothesis that myelin disruption with pharmacologic or genetic tools will exacerbate the development of limbic alpha-synucleinopathy in mice of both sexes, using a full-factorial experimental design. In nontransgenic mice with retrobulbar infusions of PFFs, dietary exposure to the established myelin disruptor cuprizone modestly increased the fraction of Triton-insoluble alpha-synuclein that was hyperphosphorylated at serine 129 (pSer129). Contrary to our hypothesis, however, cuprizone did not induce systematic, robust worsening of most pSer129+ object attributes, behavior deficits, cellular toxicity measures (NeuN+/Hoechst+ object attributes), or pan-alpha-synuclein insolubility. Similarly, PFF-induced effects on the insolubility and hyperphosphorylation of alpha-synuclein, behavior measures, and pSer129+, NeuN+, and Hoechst+ object attributes were not markedly amplified in mice heterozygous for the shiverer mutation in myelin basic protein (Mbp^+/shi), compared to wild-type littermates. Although alpha-synucleinopathy is negatively associated with select myelin markers in mice and men, the causal nature of this link thus remains to be verified, and its potential implications are discussed here.