Research Insights

Chronic environmental exposure to neurotoxic levels of the metal manganese (Mn) affects the basal ganglia system and has been linked to the etiology of Parkinsonism. Within the basal ganglia (BG), Mn primarily accumulates in the globus pallidus, resulting in dysregulation of the BG neural circuitry. As the most abundant glial cells in the CNS, astrocytes are critical for healthy brain function and are highly sensitive to Mn toxicity as the metal preferentially accumulates in astrocytes. For any neurotoxicological triggers, astrocytes are early responders and undergo a process known as “reactive astrogliosis”, characterized by morphological, molecular, and functional changes. In this context, increasing evidence suggests that Mn neurotoxicity elicits proinflammatory responses in astrocytes. However, the fundamental molecular neurotoxicological mechanisms regulating the transformation of an astrocyte’s homeostatic phenotype from quiescent to pro-inflammatory and the exact molecular regulators of astrocyte crosstalk with neurons and microglia in metal neurotoxicity remain enigmatic. In the emerging field of epitranscriptomics, the role of N6-methyladenosine (m6A) RNA modification, under the dynamic control of N6-methyltransferases, demethylases, and readers (m6A mRNA-binding proteins), in neurodegenerative diseases (NDs) is currently being explored. We recently obtained exciting new data showing that the m6A reader protein YTHDF2 is specifically downregulated by Mn in cultured human astrocyte cells and primary murine astrocytes as well as in animal models. Functional loss- and gain-of-function studies reveal an anti-inflammatory role for YTHDF2 in Mn-stimulated astrocytes, leading to a novel hypothesis that YTHDF2 may be a critical regulator impacting Mn neurotoxicity. Additional mechanistic studies identified SEK1 mRNA as a direct target of YTHDF2 and also discovered the ability of YTHDF2 to suppress the SEK1/JNK/cJun pro-inflammatory signaling axis and subsequent production and secretion of selected pro-inflammatory mediators in reactive astrocytic cultures. Very recently, we also observed a significant increase in the m6A readers YTHDF1 and YTHDF3, which can boost the translation of their respective targets. Thus, the following specific aims will be pursued to further expand our novel findings: (i) elucidate in animal models if chronic Mn exposure dysregulates YTHDF proteins in astrocytes, and whether this dysregulation contributes to Mn neurotoxicity by disrupting neuroimmune homeostasis; (ii) elucidate the pro-inflammatory signaling mechanisms underpinning YTHDF dysregulation in activated astrocytes during Mn neurotoxicity in animal models; and (iii) validate YTHDF proteins as key regulators of astrocyte-mediated immune and neuronal dysfunction in Mn neurotoxicity. Overall, we anticipate that our proposed studies will provide novel mechanistic insights into reactive astrocytic activation and neuroimmune interactions in metal neurotoxicology and will offer novel therapeutic targets to dampen the neuroinflammatory processes in environmental factor-related neurodegenerative diseases.

Funder: National Institutes of Health 

Amount: $441,529 

PI: Anumantha Kanthasamy, College of Veterinary Medicine