Rolle genetischer Manipulationen in der mangan-induzierten dopaminergen Neurodegeneration in C. elegans
Zusammenfassung der Projektergebnisse
Manganese (Mn) is an essential trace element occupying important psychological functions for human health, which is commonly found in the environment. However, overexposure can result in an irreversible condition known as manganism that shares similar neuropathology with Parkinson’s disease (PD), with overt dopaminergic (DAergic) cell loss associated with the presentation of motor and cognitive deficits. The underlying mechanisms mediating the pathophysiology of both disorders are still poorly understood. Several genes have been linked to PD, including two genes associated with the early-onset familial form participating in oxidative stress pathways: pink1 and dj1. While only 10-20% of PD cases are documented as having genetic causes, growing evidence implicates an environmental/occupational contribution whereby Mn might be a risk factor. Therefore, within the present study by using the genetically amenable Caenorhabditis elegans (C. elegans) model system, interactions between Mn and the two PD associated genes (pink1 and djr1.1 (C.elegans orthologue of dj1)) were studied. In order to study the relationship between djr1.1 or pink1 deletions and Mn sensitivity, worms with a djr1.1 deletion (tm918) or pink1 deletion (tm1779) were utilized. djr1.1 and pink1 deletion mutants exhibited altered oxidative defense responses compared to WT worms, as confirmed by inherently decreased total glutathione (GSH) levels and increased Mn-induced reactive oxygen/nitrogen species (RONS) induction. Interestingly, the djr1.1 deletion mutants showed a quicker and more robust increase in RONS induction compared to wildtype (WT) worms and pink1 deletion mutants upon exposure to Mn. This effect correlated with increased Mn uptake in the djr1.1 deletion mutants compared to WT and pink1 worms. Another gene implicated in PD pathophysiology is SNCA, which encodes for α-synuclein, the major aggregated component of Lewy body depositions. The function is still discussed controversial since it is showing neurotoxic and neuroprotective activities in PD. While C. elegans do not express α-synuclein, strains containing the djr1.1 or pink1 deletion and WT human α-synuclein were utilized. The loss of djr1.1 in these α-synuclein containing worms resulted in reduced Mn-induced RONS induction and Mn uptake compared to worms containing the djr1.1 deletion alone. For the first time, the current study provides evidence for a neuroprotective role of WT α-Syn against Mn accumulation and Mn-induced oxidative stress in the background of djr1.1 loss. Moreover, regarding DAergic neurodegeneration, while unchanged with Mn exposure, pink1 mutants expressing α-synuclein show a rescued degeneration of the architecture of the dopaminergic neurons, while α-synuclein containing djr1.1 mutants do not. This might due to the increased mRNA level of the dopamine transporter 1 (dat-1) suggesting higher extracellular dopamine levels. Taken together, this study uncovers a novel, neuroprotective role for WT human α-synuclein in attenuating Mn-induced toxicity in the background of PD-associated genes, and further supports the role of extracellular dopamine in exacerbating Mn neurotoxicity.
Projektbezogene Publikationen (Auswahl)
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Oxidative Stress Mechanisms Underlying Parkinson’s Disease-Associated Neurodegeneration in C. elegans, Int. J. Mol. Sci. 2013, 14(11), 23103-23128
S. Chakraborty, J. Bornhorst, T. T. Nguyen, M. Aschner
