The formation of oligomers and aggregates of overexpressed or mutant α-synuclein play a role in the degeneration of dopaminergic neurons in Parkinson’s disease by causing dysfunction of mitochondria, reflected in their disturbed mobility and production of ROS. The mode of action and mechanisms underlying this mitochondrial impairment is still unclear. We have induced stable expression of wild-type, A30P or A53T α-synuclein in neuronally differentiated SH-SY5Y neuroblastoma cells and studied anterograde and retrograde mitochondrial trafficking in this cell model for Parkinson’s disease. In contrast to wild-type and A30P, A53T α-synuclein significantly inhibited mitochondrial trafficking, at first retrogradely and in a later stage anterogradely. Accordingly, A53T α-synuclein also caused the highest increase in ROS production in the dysmobilized mitochondria in comparison to wild-type or A30P α-synuclein. Treatment with NAP, the eight amino acid peptide identified as the active component of activity-dependent neuroprotective protein (ADNP), completely annihilated the adverse effects of A53T on mitochondrial dynamics. Our results reveal that A53T α-synuclein (oligomers or aggregates) leads to the inhibition of mitochondrial trafficking, which can be rescued by NAP, suggesting the involvement of microtubule disruption in the pathophysiology of Parkinson’s disease.Electronic supplementary materialThe online version of this article (doi:10.1007/s00221-016-4836-9) contains supplementary material, which is available to authorized users.
STUDY QUESTION Does lifestyle intervention consisting of an energy-restricted diet, enhancement of physical activity, and motivational counseling prior to IVF improve embryo utilization rate (EUR) and cumulative live birth rate (CLBR) in women with obesity? SUMMARY ANSWER A 6-month lifestyle intervention preceding IVF improved neither EUR nor CLBR in women with obesity in the first IVF treatment cycle where at least one oocyte was retrieved. WHAT IS KNOWN ALREADY A randomized controlled trial (RCT) evaluating the efficacy of a low caloric liquid formula diet (LCD) preceding IVF in women with obesity was unable to demonstrate an effect of LCD on embryo quality and live birth rate: in this study, only one fresh embryo transfer (ET) or, in case of freeze-all strategy, the first transfer with frozen-thawed embryos was reported. We hypothesized that any effect on embryo quality of a lifestyle intervention in women with obesity undergoing IVF treatment is better revealed by EUR and CLBR after transfer of all fresh and frozen-thawed embryos. STUDY DESIGN, SIZE, DURATION This is a nested cohort study within an RCT, the LIFEstyle study. The original study examined whether a 6-month lifestyle intervention prior to infertility treatment in women with obesity improved live birth rate, compared to prompt infertility treatment within 24 months after randomization. In the original study between 2009 and 2012, 577 (three women withdrew informed consent) women with obesity and infertility were assigned to a lifestyle intervention followed by infertility treatment (n = 289) or to prompt infertility treatment (n = 285). PARTICIPANTS/MATERIALS, SETTING, METHODS Only participants from the LIFEstyle study who received IVF treatment were eligible for the current analysis. In total 137 participants (n = 58 in the intervention group, and n = 79 in the control group) started the first cycle. In 25 participants, the first cycle was cancelled prior to oocyte retrieval mostly due to poor response. Sixteen participants started a second or third consecutive cycle. The first cycle with successful oocyte retrieval was used for this analysis, resulting in analysis of 51 participants in the intervention group and 72 participants in the control group. Considering differences in embryo scoring methods and ET day strategy between IVF centers, we used EUR as a proxy for embryo quality. EUR was defined as the proportion of inseminated/injected oocytes per cycle that was transferred or cryopreserved as an embryo. Analysis was performed per cycle and per oocyte/embryo. CLBR was defined as the percentage of participants with at least one live birth from the first fresh and subsequent frozen-thawed ET(s). In addition, we calculated the Z-score for singleton neonatal birthweight and compared these outcomes between the two groups. MAIN RESULTS AND THE ROLE OF CHANCE The overall mean age was 31.6 years and the mean BMI was 35.4 ± 3.2 kg/m2 in the intervention group, and 34.9 ± 2.9 kg/m2 in the control group. The weight change at 6 months was in favor of the intervention group (mean difference in kg versus the control group: -3.14, 95% CI: -5.73 to -0.56). The median (Q25; Q75) number of oocytes retrieved was 4.00 (2.00; 8.00) in the intervention group versus 6.00 (4.00; 9.75) in the control group, and was not significantly different, as was the number of oocytes inseminated/injected (4.00 [2.00; 8.00] versus 6.00 [3.00; 8.75]), normal fertilized embryos (2.00 [0.50; 5.00] versus 3.00 [1.00; 5.00]), and the number of cryopreserved embryos (2.00 [1.25; 4.75] versus 2.00 [1.00; 4.00]). The median (Q25; Q75) EUR was 33.3% (12.5%; 60.0%) in the intervention group and 33.3% (16.7%; 50.0%) in the control group in the per cycle analysis (adjusted B: 2.7%, 95% CI: -8.6% – 14.0%). In the per oocyte/embryo analysis, in total 280 oocytes were injected or inseminated in the intervention group, 113 were utilized (transferred or cryopreserved, EUR = 40.4%); in the control group EUR was 30.8% (142/461). The lifestyle intervention did not significantly improve EUR (adjusted Odds Ratio [OR]: 1.36, 95% CI: 0.94 – 1.98) in the per oocyte/embryo analysis, taking into account the interdependency of the oocytes per participant. CLBR was not significantly different between the intervention group and the control group after adjusting for type of infertility (male factor and unexplained) and smoking (27.5% versus 22.2%, adjusted OR: 1.03, 95% CI: 0.43 – 2.47). Singleton neonatal birthweight and Z-score were not significantly different between the two groups. LIMITATIONS, REASONS FOR CAUTION This study is a nested cohort study within an RCT, and no power calculation was performed. The randomization was not stratified for indicated treatment, and although we corrected our analyses for baseline differences, there may be residual confounding. The limited absolute weight loss and the short duration of the lifestyle intervention might be insufficient to affect EUR and CLBR. WIDER IMPLICATIONS OF THE FINDINGS Our data do not support the hypothesis of a beneficial short-term effect of lifestyle intervention on EUR and CLBR after IVF in women with obesity, although more studies are needed as there may be a potential clinically relevant effect on EUR. STUDY FUNDING/COMPETING INTEREST(S) The study was supported by a grant from ZonMw, the Dutch Organization for Health Research and Development (50–50110-96–518). Annemieke Hoek has received an unrestricted educational grant from Ferring pharmaceuticals BV, The Netherlands. Ben W. J. Mol is supported by a NHMRC Investigator grant (GNT1176437). Ben W. J. Mol reports consultancy for Guerbet, has been a member of the ObsEva advisory board and hold Stock options for ObsEva. Ben W. J. Mol has received research funding from Guerbet, Ferring and Merck. Frank J.M. Broekmans reports personal fees from member of the external advisory board for Merck Serono and grants from research support grant Merck Serono, outside the submitted work. TRIAL REGISTRATION NUMBER The LIFEstyle RCT was registered at the Dutch trial registry (NTR 1530). https://www.trialregister.nl/trialreg/admin/rctview.asp?TC = 1530.
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