O papel do manganês na modulação de neurotransmissores e seu impacto no desenvolvimento da poliglutamina em Caenorhabditis elegans modelo para doença de Huntington​

Abstract

Manganese (Mn) is a naturally occurring metal essential for several metabolic processes. However, at high concentrations, it can cause neurotoxicity. The mechanisms underlying this neurotoxicity include changes in dopamine metabolism, mitochondrial dysfunctions, and induction of cell death. Additionally, previous investigations have shown that the homeostasis of this metal is compromised in the brains of patients affected by neurodegenerative diseases, such as Huntington's disease (HD). Given the duality of manganese in the nervous system, it is necessary to understand both the mechanisms by which Mn becomes essential for the neurotransmitter system and the toxic effects resulting from its exposure at higher-than-ideal concentrations. Elucidating the mechanisms of Mn toxicity is also a pertinent approach to clarify the role of this metal in the development of neurodegenerative diseases. Therefore, the first part of this study addresses the main effects of Mn on neurotransmitter systems. In this literature review, we report how Mn accumulates in certain areas of the brain, leading to dopamine depletion, reduced cholinergic signaling, and decreased glutamate reuptake, resulting in neurotoxicity. In the second part of this thesis, we investigated whether exposure to Mn influences the development of HD using the nematode Caenorhabditis elegans as an experimental model. Using HD models (strains AM101, AM141, and HA759, which express mutant human polyglutamine in neurons or muscles) and acute exposure of 30 minutes in liquid MnCl2 medium (25 mM), it was observed that Mn affects metal transport, altering their homeostasis in HD strains. Furthermore, evidence of damage to the cholinergic, dopaminergic, and glutamatergic systems was found through behavioral modifications and a reduction in the formation of polyglutamine (polyQ) protein aggregates. In this context, this study provided a deeper understanding of the mechanisms related to Mn toxicity in neurotransmitters and its neurodegenerative potential associated with the development of HD in an invertebrate model, C. elegans​.