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

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

Multiomic ALS signatures highlight sex differences and molecular subclusters and identify the MAPK pathway as therapeutic target

Abstract Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease and lacks effective disease-modifying treatments. Here, we performed a multiomic analysis of the prefrontal cortex of 51 patients with sporadic ALS and 50 control subjects, as well as four transgenic mouse models of C9orf72-, SOD1-, TDP-43-, and FUS-ALS to characterize early and sex-specific disease mechanisms in ALS. Integrated analyses of transcriptomes, (phospho)proteomes, and miRNAomes revealed more pronounced changes in male patients. We identified transcriptome-based human ALS subclusters driven by the immune response, extracellular matrix, mitochondrial respiration, and RNA metabolism. The molecular signatures of human subclusters were reflected in specific mouse models. Individual and integrative multiomics analyses highlighted the mitogen-activated protein kinase pathway as an early disease-relevant mechanism. Its modulation by trametinib in vitro and in vivo validated that mitogen-activated protein kinase kinase 2 is a promising therapeutic target with beneficial effects in female patients