Trichloroethylene and its metabolite TaClo lead to degeneration of substantia nigra dopaminergic neurones: Effects in wild type and human A30P mutant α-synuclein mice

P.C Keane,P.S Hanson,L Patterson,P.G Blain,P Hepplewhite,A.A Khundakar,S.J Judge,P.J Kahle,F.E.N Lebeau,C.M Morris

doi:10.1016/j.neulet.2019.134437

P.C Keane, P.S Hanson + Show 8 more

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https://doi.org/10.1016/j.neulet.2019.134437

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Abstract

Parkinson’s disease (PD) is characterised pathologically by degeneration of the dopaminergic (DA) neurones of the substantia nigra pars compacta (SNpc) and the presence of α-synuclein containing Lewy body inclusions. Trichloroethylene (TCE) has been suggested as a potential environmental chemical that may contribute to the development of PD, via conversion to the neurotoxin, 1-Trichloromethyl-1,2,3,4-tetrahydro-β-carboline (TaClo). We investigated the effect of an 8 week exposure to TCE or TaClo on wild type and, as an experimental model of PD, A30P mutant α-synuclein overexpressing mice using a combination of behaviour and pathology. TCE or TaClo exposure caused significant DA neuronal loss within the SNpc in both wild type and transgenic mice. Cell numbers were lower in A30P animals than wild type, however, no additive effect of TCE or TaClo exposure and A30P overexpression was found. TCE or TaClo did not appear to lead to acceleration of motor or cognitive deficits in either wild type or A30P mutant mice, potentially because of the modest reductions of DA neuronal number in the SNpc. Our results do however suggest that TCE exposure could be a possible factor in development of PD like changes following exposure.

Highlights

Parkinson’s disease (PD) is the leading cause of neurodegenerative motor impairment and is characterised by progressive loss of the dopaminergic (DA) neurones of the substantia nigra pars compacta (SNpc)
No significant differences between treatment groups and no significant effect of treatment over time was found in either A30P mutant or wild type mice, but there was a significant decrease in performance over time across all groups (Fig. 1)
DA neurone numbers in this study showed a significant decrease in both wild type and A30P mice exposed to TCE and TaClo

Summary

Introduction

Parkinson’s disease (PD) is the leading cause of neurodegenerative motor impairment and is characterised by progressive loss of the dopaminergic (DA) neurones of the substantia nigra pars compacta (SNpc). One current suggestion is that in genetically predisposed individuals, exposure to an unidentified environmental chemical(s) leads to cell death in the enteric nervous system and spread of alpha-synuclein pathology to the central nervous system and the SNpc [2]. Trichloroethylene (TCE), a commonly used industrial solvent, is one potential environmental chemical that may contribute to the development of PD and similar forms of parkinsonism. TaClo can cause up to 50% cell death in primary DA neurones cultures [12], as well as in vivo exposure, leading to a reduction in DA metabolism [13] and altered locomotor activity [14,15,16]. How TCE or TaClo might lead to parkinsonism is unclear since both potentially can cause peripheral neuronal damage and consequent

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