Joppe KDN, Tatenhorst L, Caldi Gomes L, Zhang S, Parvaz M, Carboni E, Roser AE, El DeBakey H, Bähr M, Vogel-Mikuš K, Ip CW, Becker S, Zweckstetter M, Lingor P
Journal of Neurochemistry
J Neurochem. 2021 Jun 27.
Regional iron accumulation and α-synuclein (α-syn) spreading pathology within the central nervous system are common pathological findings in Parkinson’s disease (PD). Whereas iron is known to bind to α-syn, facilitating its aggregation and regulating α-syn expression, it is unclear if and how iron also modulates α-syn spreading. To elucidate the influence of iron on the propagation of α-syn pathology, we investigated α-syn spreading after stereotactic injection of α-syn preformed fibrils (PFFs) into the striatum of mouse brains after neonatal brain iron enrichment. C57Bl/6J mouse pups received oral gavage with 60, 120 or 240 mg/kg carbonyl-iron or vehicle between postnatal day 10 and 17. At 12 weeks of age, intrastriatal injections of 5 µg PFFs were performed to induce seeding of α-syn aggregates. At 90 days post-injection, PFFs injected mice displayed long-term memory deficits, without affection of motor behavior. Interestingly, quantification of α-syn phosphorylated at S129 showed reduced α-syn pathology and attenuated spreading to connectome-specific brain regions after brain iron enrichment. Furthermore, PFFs injection caused intrastriatal microglia accumulation, which was alleviated by iron in a dose-dependent way. In primary cortical neurons in a microfluidic chamber model in vitro, iron application did not alter transsynaptic α-syn propagation, possibly indicating an involvement of non-neuronal cells in this process. Our study suggests that α-syn PFFs may induce cognitive deficits in mice independent of iron. However, a redistribution of α-syn aggregate pathology and reduction of striatal microglia accumulation in the mouse brain may be mediated via iron-induced alterations of the brain connectome.