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  Brain iron enrichment attenuates α-synuclein spreading after injection of preformed fibrils

Dauer née Joppe, K., Tatenhorst, L., Caldi Gomes, L., Zhang, S., Parvaz, M., Carboni, E., et al. (2021). Brain iron enrichment attenuates α-synuclein spreading after injection of preformed fibrils. Journal of Neurochemistry, 159(3), 554-573. doi:10.1111/jnc.15461.

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Dauer née Joppe, K., Author
Tatenhorst, L., Author
Caldi Gomes, L., Author
Zhang, S., Author
Parvaz, M., Author
Carboni, E., Author
Roser, A.-E., Author
El DeBakey, H., Author
Bähr, M., Author
Vogel-Mikuš, K., Author
Ip, C. W., Author
Becker, S.1, Author              
Zweckstetter, M.2, Author              
Lingor, P., Author
Affiliations:
1Department of NMR Based Structural Biology, MPI for biophysical chemistry, Max Planck Society, ou_578567              
2Research Group of Protein Structure Determination using NMR, MPI for biophysical chemistry, Max Planck Society, ou_578571              

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 Abstract: 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 remains 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 days 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 trans-synaptic 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.

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Language(s): eng - English
 Dates: 2021-06-272021-11
 Publication Status: Published in print
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 Rev. Type: Peer
 Identifiers: DOI: 10.1111/jnc.15461
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Title: Journal of Neurochemistry
Source Genre: Journal
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Pages: - Volume / Issue: 159 (3) Sequence Number: - Start / End Page: 554 - 573 Identifier: -