α-Synuclein and manganese elicit distinct transcriptomic alterations that disrupt microglial homeostasis and sustain inflammasome activation Naveen Kondru#, Sireesha Manne#, Emir Malovic#, Vellareddy Anantharam#, and Arthi Kanthasamy #, Anumantha Kanthasamy#* #Department of Biomedical Sciences, College of Veterinary Medicine, Iowa State University, Ames, IA 50011, USA *Corresponding author: firstname.lastname@example.org Converging evidence suggests that microglial dysfunction is a central player in the pathogenesis of neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal dementia (FTD). Risk factors such as metal exposure, pesticides, and peripheral inflammation (gut, lungs) have been implicated in the etiology of PD. The divalent metal Manganese (Mn) can cross the blood-brain barrier and is linked to Parkinsonism. We hypothesized that Mn interacts synergistically with α-synuclein (α-syn) to trigger destructive neuroinflammatory processes. Therefore, we performed transcriptome analysis of microglia in response to Mn and α-syn and their co-treatments to identify the key genes and signaling pathways underpinning the inflammatory response. We further validated the identified targets using quantitative real-time PCR and immunoblots. The α-syn treatment predominately activated innate immune response-related genes involving cytokine and chemokine imbalances and their associated signaling pathways (TNF, NF-kB, and TLR signaling). In contrast, Mn caused distinct changes to pathways related to cellular senescence, NOD-like receptor signaling, apoptosis, HIF-1 signaling, and pyrimidine metabolism. Mn and α-syn co-treatment caused major perturbations in Rho GTPase signaling and inflammasome activation. Co-treatment also caused profound changes in transcripts that triggered microglia to switch to their more cytotoxic, M1 phenotype. Top upregulated genes were Il6, Urah, Nos2, Lcn2 and Csf3, while Slc14a1 transcripts were down-regulated. Overall, our study identifies distinct genes and pathways elicited by α-syn and Mn that perturb microglial homeostasis.
These findings also suggest that environmental factors can induce neuroimmune transformations that possibly alter the course of neurodegenerative processes. (Funding acknowledgement: NIH grants ES026892, NS088206, and W. Eugene Linda Lloyd Endowed Chair)
Credits: None available.
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