Manganese exposure exacerbates progressive motor deficits and neurodegeneration in the MitoPark mouse model of Parkinson’s disease: Relevance to gene and environment interactions in metal neurotoxicity

Abstract

Parkinson's disease (PD) is now recognized as a neurodegenerative condition caused by a complex interplay of genetic and environmental influences. Chronic manganese (Mn) exposure has been implicated in the development of PD. Since mitochondrial dysfunction is associated with PD pathology as well as Mn neurotoxicity, we investigated whether Mn exposure augments mitochondrial dysfunction and neurodegeneration in the nigrostriatal dopaminergic system using a newly available mitochondrially defective transgenic mouse model of PD, the MitoPark mouse. This unique PD model recapitulates key features of the disease including progressive neurobehavioral changes and neuronal degeneration. We exposed MitoPark mice to a low dose of Mn (10mg/kg, p.o.) daily for 4 weeks starting at age 8 wks and then determined the behavioral, neurochemical and histological changes. Mn exposure accelerated the rate of progression of motor deficits in MitoPark mice when compared to the untreated MitoPark group. Mn also worsened olfactory function in this model. Most importantly, Mn exposure intensified the depletion of striatal dopamine and nigral TH neuronal loss in MitoPark mice. The neurodegenerative changes were accompanied by enhanced oxidative damage in the striatum and substantia nigra (SN) of MitoPark mice treated with Mn. Furthermore, Mn-treated MitoPark mice had significantly more oligomeric protein and IBA-1-immunoreactive microglia cells, suggesting Mn augments neuroinflammatory processes in the nigrostriatal pathway. To further confirm the direct effect of Mn on impaired mitochondrial function, we also generated a mitochondrially defective dopaminergic cell model by knocking out the TFAM transcription factor by using a CRISPR-Cas9 gene-editing method. Seahorse mitochondrial bioenergetic analysis revealed that Mn decreases mitochondrial basal and ATP-linked respiration in the TFAM KO cells. Collectively, our results reveal that Mn can augment mitochondrial dysfunction to exacerbate nigrostriatal neurodegeneration and PD-related behavioral symptoms. Our study also demonstrates that the MitoPark mouse is an excellent model to study the gene-environment interactions associated with mitochondrial defects in the nigral dopaminergic system as well as to evaluate the contribution of potential environmental toxicant interactions in a slowly progressive model of Parkinsonism.

Neurotoxicity of manganese: Indications for future research and public health intervention from the Manganese 2016 conference

“…The role of mitochondria in Mn-induced neurotoxicity was also advanced by Langley and collaborators. Taking advantage of a newly available mitochondrially defective transgenic mouse model of Parkinson’s disease (PD), the MitoPark mouse, this group corroborates gene environment interactions associated with mitochondrial defects in the nigral dopaminergic system (Langley et al, 2018). Loss of ATP13A2 function in ATP13A2-deficient mice is also shown as a risk factor for increased sensitivity to Mn in vivo (Fleming et al, 2018).…”

Mitochondrial Dysfunction Induces Epigenetic Dysregulation by H3K27 Hyperacetylation to Perturb Active Enhancers in Parkinson’s Disease Models

“…TFAM (transcription factor A, mitochondrial) functions in genome transcription regulation and controls mitochondrial biogenesis (Miyazaki et al, 2012). Conditionally knocking out TFAM in DAergic cells produces mitochondrial dysfunction, which in mice leads progressively to a suite of neural and behavioral deficits that recapitulate PD (Langley et al, 2018). Using a CRISPR-Cas9 gene-editing method, we generated a stable TFAM-KO N27 cell line.…”

Effect of trehalose on manganese‐induced mitochondrial dysfunction and neuronal cell damage in mice

“…In addition, Mn is an important occupational toxicant and environmental pollutant. Chronic Mn exposure leads to neurotoxicity, which is characterized by Parkinsonian‐like symptoms resulting from impairment in the extrapyramidal motor system of the basal ganglia referred to as manganism . Mn toxicity is mainly resulted from environmental exposures, particularly airborne exposure.…”

“…Chronic Mn exposure leads to neurotoxicity, which is characterized by Parkinsonian-like symptoms resulting from impairment in the extrapyramidal motor system of the basal ganglia referred to as manganism. 2 Mn toxicity is mainly resulted from environmental exposures, particularly airborne exposure. Typical airborne exposure routes are from automobile exhaust and occupational exposure (mining, welding and battery manufacture).…”