Genetic-based, Differential Susceptibility To Paraquat Neurotoxicity In Mice
Open Access
- Author:
- Yin, Lina
- Graduate Program:
- Neuroscience
- Degree:
- Doctor of Philosophy
- Document Type:
- Dissertation
- Date of Defense:
- October 08, 2012
- Committee Members:
- Byron C Jones, Dissertation Advisor/Co-Advisor
Byron C Jones, Committee Chair/Co-Chair
David John Vandenbergh, Committee Member
James Robert Connor, Committee Member
Laura Klein, Committee Member
Paul Allen Bartell, Committee Member
Eric Richfield, Special Member - Keywords:
- Parkinson's disease
Paraquat
Iron
Genetics - Abstract:
- The etiology of sporadic Parkinson’s disease (sPD) is currently unclear and the most plausible hypothesis states sPD is the result of environmental risk factors acting on genetically susceptible individuals. Those risk factors include metals, diet and pesticides. One of the latter, paraquat (PQ) is an herbicide used world-wide in agriculture. Paraquat has been shown in experimental animals and in vitro to destroy dopaminergic neurons in the substantia nigra. Dopaminergic neuron loss in the substantia nigra is a major pathological hallmark of sPD. There are epidemiological data that implicate PQ to be an environmental risk factor for sPD; however the data are inconsistent. One possible reason for the inconsistency is that there is likely, genetic-based, individual variability in susceptibility to PQ neurotoxicity related PD. In this thesis, we report differential sensitivity to PQ neurotoxicity in inbred strains of mice. This differential sensitivity was shown by experimental results on the effects of PQ on dopaminergic neuron loss in the substantia nigra and by differential gene expression in response to PQ in the ventral midbrain, the area that contains the substantia nigra. Somewhat surprisingly, gene expression results implicated iron-related protein genes as associated to high susceptibility to PQ neurotoxicity and we also found that in the susceptible strains of mice, PQ increased iron content in the ventral midbrain. The results indicate that iron and PQ act cooperatively in neurotoxicity and that the key to understanding individual differences in PQ (and likely other toxicants) susceptibility may lie in genetic differences in liability in iron management systems in the ventral midbrain.