Dietary influence on central nervous system myelin production, injury, and regeneration.

Oligodendrocytes not only produce myelin to facilitate nerve impulse conduction, but are also essential metabolic partners of the axon. Oligodendrocyte loss and myelin destruction, as occurs in multiple sclerosis (MS), leaves axons vulnerable to degeneration and permanent neurological deficits ensue. Many studies now propose that lifestyle factors such as diet may impact demyelinating conditions, including MS. Most prior reviews have focused on the regulatory role of diet in the inflammatory events that drive MS pathogenesis, however the potential for dietary factors to modulate oligodendrocyte biology, myelin injury and myelin regeneration remain poorly understood. Here we review the current evidence from clinical and animal model studies regarding the impact of diet or dietary factors on myelin integrity and other pathogenic features of MS. Some limited evidence exists that certain foods may decrease risk or influence the progression of MS, such as increased intake of fish or polyunsaturated fatty acids, caloric restriction and fasting-mimicking diets. In addition, evidence suggests adolescent obesity or insufficient vitamin D levels increase the risk for developing MS. However, no clear or consistent evidence exists that dietary components exacerbate disease progression. Cumulatively, current evidence highlights the need for more extensive clinical trials to validate dietary effects on MS and to identify diets or supplements that may be beneficial as food-based strategies in the management of MS alone or in combination with conventional disease modifying therapies.

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.

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.