Alterations in Energy/Redox Metabolism Induced by Mitochondrial and Environmental Toxins: A Specific Role for Glucose-6-Phosphate-Dehydrogenase and the Pentose Phosphate Pathway in Paraquat Toxicity

Parkinson’s disease (PD) is a multifactorial disorder with a complex etiology including genetic risk factors, environmental exposures, and aging. While energy failure and oxidative stress have largely been associated with the loss of dopaminergic cells in PD and the toxicity induced by mitochondrial/environmental toxins, very little is known regarding the alterations in energy metabolism associated with mitochondrial dysfunction and their causative role in cell death progression. In this study, we investigated the alterations in the energy/redox-metabolome in dopaminergic cells exposed to environmental/mitochondrial toxins (paraquat, rotenone, 1-methyl-4-phenylpyridinium [MPP+], and 6-hydroxydopamine [6-OHDA]) in order to identify common and/or different mechanisms of toxicity. A combined metabolomics approach using nuclear magnetic resonance (NMR) and direct-infusion electrospray ionization mass spectrometry (DI-ESI-MS) was used to identify unique metabolic profile changes in response to these neurotoxins. Paraquat exposure induced the most profound alterations in the pentose phosphate pathway (PPP) metabolome. 13C-glucose flux analysis corroborated that PPP metabolites such as glucose-6-phosphate, fructose-6-phosphate, glucono-1,5-lactone, and erythrose-4-phosphate were increased by paraquat treatment, which was paralleled by inhibition of glycolysis and the TCA cycle. Proteomic analysis also found an increase in the expression of glucose-6-phosphate dehydrogenase (G6PD), which supplies reducing equivalents by regenerating nicotinamide adenine dinucleotide phosphate (NADPH) levels. Overexpression of G6PD selectively increased paraquat toxicity, while its inhibition with 6-aminonicotinamide inhibited paraquat-induced oxidative stress and cell death. These results suggest that paraquat “hijacks” the PPP to increase NADPH reducing equivalents and stimulate paraquat redox cycling, oxidative stress, and cell death. Our study clearly demonstrates that alterations in energy metabolism, which are specific for distinct mitochondiral/environmental toxins, are not bystanders to energy failure but also contribute significant to cell death progression

Words that move us.: The effects of sentences on body sway

According to the embodied cognition perspective, cognitive systems and perceptuo-motor systems are deeply intertwined and exert a causal effect on each other. A prediction following from this idea is that cognitive activity can result in subtle changes in observable movement. In one experiment, we tested whether reading various sentences resulted in changes in postural sway. Sentences symbolized various human activities involving high, low, or no physical effort. Dutch participants stood upright on a force plate, measuring the body center of pressure, while reading a succession of sentences. High physical effort sentences resulted in more postural sway (greater SD) than low physical effort sentences. This effect only showed up in medio-lateral sway but not anterio-posterior sway. This suggests that sentence comprehension was accompanied by subtle motoric activity, likely mirroring the various activities symbolized in the sentences. We conclude that semantic processing reaches the motor periphery, leading to increased postural activity

Cycling at Altitude: Lower Absolute Power Output as the Main Cause of Lower Gross Efficiency

Background: Although cyclists often compete at altitude, the effect of altitude on gross efficiency (GE) remains inconclusive. Purpose: To investigate the effect of altitude on GE at the same relative exercise intensity and at the same absolute power output (PO) and to determine the effect of altitude on the change in GE during high-intensity exercise. Methods: Twenty-one trained men performed 3 maximal incremental tests and 5 GE tests at sea level, 1500 m, and 2500 m of acute simulated altitude. The GE tests at altitude were performed once at the same relative exercise intensity and once at the same absolute PO as at sea level. Results: Altitude resulted in an unclear effect at 1500 m (−3.8%; ±3.3% [90% confidence limit]) and most likely negative effect at 2500 m (−6.3%; ±1.7%) on pre-GE, when determined at the same relative exercise intensity. When pre-GE was determined at the same absolute PO, unclear differences in GE were found (−1.5%; ±2.6% at 1500 m; −1.7%; ±2.4% at 2500 m). The effect of altitude on the decrease in GE during high-intensity exercise was unclear when determined at the same relative exercise intensity (−0.4%; ±2.8% at 1500 m; −0.7%; ±1.9% at 2500 m). When GE was determined at the same absolute PO, altitude resulted in a substantially smaller decrease in GE (2.8%; ±2.4% at 1500 m; 5.5%; ±2.9% at 2500 m). Conclusion: The lower GE found at altitude when exercise is performed at the same relative exercise intensity is mainly caused by the lower PO at which cyclists exercis

Cycling at altitude: Lower absolute power output as the main cause of lower gross efficiency

Background: Although cyclists often compete at altitude, the effect of altitude on gross efficiency (GE) remains inconclusive. Purpose: To investigate the effect of altitude on GE at the same relative exercise intensity and at the same absolute power output (PO) and to determine the effect of altitude on the change in GE during high-intensity exercise. Methods: Twenty-one trained men performed 3 maximal incremental tests and 5 GE tests at sea level, 1500 m, and 2500 m of acute simulated altitude. The GE tests at altitude were performed once at the same relative exercise intensity and once at the same absolute PO as at sea level. Results: Altitude resulted in an unclear effect at 1500 m (−3.8%; ±3.3% [90% confidence limit]) and most likely negative effect at 2500 m (−6.3%; ±1.7%) on pre-GE, when determined at the same relative exercise intensity. When pre-GE was determined at the same absolute PO, unclear differences in GE were found (−1.5%; ±2.6% at 1500 m; −1.7%; ±2.4% at 2500 m). The effect of altitude on the decrease in GE during high-intensity exercise was unclear when determined at the same relative exercise intensity (−0.4%; ±2.8% at 1500 m; −0.7%; ±1.9% at 2500 m). When GE was determined at the same absolute PO, altitude resulted in a substantially smaller decrease in GE (2.8%; ±2.4% at 1500 m; 5.5%; ±2.9% at 2500 m). Conclusion: The lower GE found at altitude when exercise is performed at the same relative exercise intensity is mainly caused by the lower PO at which cyclists exercise

Astrocyte reactivity in a mouse model of SCN8A epileptic encephalopathy

ObjectiveSCN8A epileptic encephalopathy is caused predominantly by de novo gain-of-function mutations in the voltage-gated sodium channel Nav1.6. The disorder is characterized by early onset of seizures and developmental delay. Most patients with SCN8A epileptic encephalopathy are refractory to current anti-seizure medications. Previous studies determining the mechanisms of this disease have focused on neuronal dysfunction as Nav1.6 is expressed by neurons and plays a critical role in controlling neuronal excitability. However, glial dysfunction has been implicated in epilepsy and alterations in glial physiology could contribute to the pathology of SCN8A encephalopathy. In the current study, we examined alterations in astrocyte and microglia physiology in the development of seizures in a mouse model of SCN8A epileptic encephalopathy.MethodsUsing immunohistochemistry, we assessed microglia and astrocyte reactivity before and after the onset of spontaneous seizures. Expression of glutamine synthetase and Nav1.6, and Kir4.1 channel currents were assessed in astrocytes in wild-type (WT) mice and mice carrying the N1768D SCN8A mutation (D/+).ResultsAstrocytes in spontaneously seizing D/+ mice become reactive and increase expression of glial fibrillary acidic protein (GFAP), a marker of astrocyte reactivity. These same astrocytes exhibited reduced barium-sensitive Kir4.1 currents compared to age-matched WT mice and decreased expression of glutamine synthetase. These alterations were only observed in spontaneously seizing mice and not before the onset of seizures. In contrast, microglial morphology remained unchanged before and after the onset of seizures.SignificanceAstrocytes, but not microglia, become reactive only after the onset of spontaneous seizures in a mouse model of SCN8A encephalopathy. Reactive astrocytes have reduced Kir4.1-mediated currents, which would impair their ability to buffer potassium. Reduced expression of glutamine synthetase would modulate the availability of neurotransmitters to excitatory and inhibitory neurons. These deficits in potassium and glutamate handling by astrocytes could exacerbate seizures in SCN8A epileptic encephalopathy. Targeting astrocytes may provide a new therapeutic approach to seizure suppression.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/172811/1/epi412564_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/172811/2/epi412564.pd

Postictal Death Is Associated with Tonic Phase Apnea in a Mouse Model of Sudden Unexpected Death in Epilepsy

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/167472/1/ana26053_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/167472/2/ana26053.pd