Involvment of Cytosolic and Mitochondrial GSK-3β in Mitochondrial Dysfunction and Neuronal Cell Death of MPTP/MPP+-Treated Neurons

Aberrant mitochondrial function appears to play a central role in dopaminergic neuronal loss in Parkinson's disease (PD). 1-methyl-4-phenylpyridinium iodide (MPP+), the active metabolite of N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), is a selective inhibitor of mitochondrial complex I and is widely used in rodent and cell models to elicit neurochemical alterations associated with PD. Recent findings suggest that Glycogen Synthase Kinase-3β (GSK-3β), a critical activator of neuronal apoptosis, is involved in the dopaminergic cell death. In this study, the role of GSK-3β in modulating MPP+-induced mitochondrial dysfunction and neuronal death was examined in vivo, and in two neuronal cell models namely primary cultured and immortalized neurons. In both cell models, MPTP/MPP+ treatment caused cell death associated with time- and concentration-dependent activation of GSK-3β, evidenced by the increased level of the active form of the kinase, i.e. GSK-3β phosphorylated at tyrosine 216 residue. Using immunocytochemistry and subcellular fractionation techniques, we showed that GSK-3β partially localized within mitochondria in both neuronal cell models. Moreover, MPP+ treatment induced a significant decrease of the specific phospho-Tyr216-GSK-3β labeling in mitochondria concomitantly with an increase into the cytosol. Using two distinct fluorescent probes, we showed that MPP+ induced cell death through the depolarization of mitochondrial membrane potential. Inhibition of GSK-3β activity using well-characterized inhibitors, LiCl and kenpaullone, and RNA interference, prevented MPP+-induced cell death by blocking mitochondrial membrane potential changes and subsequent caspase-9 and -3 activation. These results indicate that GSK-3β is a critical mediator of MPTP/MPP+-induced neurotoxicity through its ability to regulate mitochondrial functions. Inhibition of GSK-3β activity might provide protection against mitochondrial stress-induced cell death

The Scandinavian Solutions for Wellness study - a two-arm observational study on the effectiveness of lifestyle intervention on subjective well-being and weight among persons with psychiatric disorders

<p>Abstract</p> <p>Background</p> <p>Solutions for Wellness (SfW) is an educational 3-month program concerning nutrition and exercise for persons with psychiatric disorders on psychotropic medication, who have weight problems. This observational study assessed the impact of SfW on subjective well-being, weight and waist circumference (WC).</p> <p>Methods</p> <p>Data was collected at 49 psychiatric clinics. Where the SfW program was offered patients could enter the intervention group; where not, the control group. Subjective well-being was measured by the Subjective Well-being under Neuroleptics scale (SWN), at baseline, at the end of SfW participation, and at a follow-up 6 months after baseline. Demographic, disease and treatment data was also collected.</p> <p>Results</p> <p>314 patients enrolled in the SfW group, 59 in the control group. 54% of the patients had schizophrenia, 67% received atypical antipsychotics, 56% were female. They averaged 41 ± 12.06 years and had a BMI of 31.4 ± 6.35. There were significant differences at baseline between groups for weight, SWN total score and other factors. Stepwise logistic models controlling for baseline covariates yielded an adjusted non-significant association between SfW program participation and response in subjective well-being (SWN increase). However, statistically significant associations were found between program participation and weight-response (weight loss or gain < 1 kg) OR = 2; 95% CI [1.1; 3.7] and between program participation and WC-response (WC decrease or increase < 2 cm) OR = 5; 95% CI [2.4; 10.3]), at 3 months after baseline.</p> <p>Conclusions</p> <p>SfW program participation was associated with maintaining or decreasing weight and WC but not with improved subjective well-being as measured with the SWN scale.</p

Evolutionary success of prokaryotes

How can the evolutionary success of prokaryotes be explained ? How did they manage to survive conditions that have fluctuated, with drastic events over 3.5 billion years ? Which significant metabolisms and mechanisms have appeared over the course of evolution that have permitted them to survive the most inhospitable conditions from the physicochemical point of view ? In a 'Red Queen Race', prokaryotes have always run sufficiently fast to adapt to constraints imposed by the environment and the other living species with which they have established interactions. If the criterion retained to define the level of evolution of an organism is its capacity to survive and to yield the largest number of offsprings, prokaryotes must be considered highly evolved organisms