MANF Inhibits α-Synuclein Accumulation through Activation of Autophagic Pathways.

Progressive accumulation of misfolded SNCA/α-synuclein is key to the pathology of Parkinson's disease (PD). Drugs aiming at degrading SNCA may be an efficient therapeutic strategy for PD. Our previous study showed that mesencephalic astrocyte-derived neurotrophic factor (MANF) facilitated the removal of misfolded SNCA and rescued dopaminergic (DA) neurons, but the underlying mechanisms remain unknown. In this study, we showed that AAV8-MANF relieved Parkinsonian behavior in rotenone-induced PD model and reduced SNCA accumulation in the substantia nigra. By establishing wildtype (WT) SNCA overexpression cellular model, we found that chaperone-mediated-autophagy (CMA) and macroautophagy were both participated in MANF-mediated degradation of SNCAWT. Nuclear factor erythroid 2-related factor (Nrf2) was activated to stimulating macroautophagy activity when CMA pathway was impaired. Using A53T mutant SNCA overexpression cellular model to mimic CMA dysfunction situation, we concluded that macroautophagy rather than CMA was responsible to the degradation of SNCAA53T, and this degradation was mediated by Nrf2 activation. Hence, our findings suggested that MANF has potential therapeutic value for PD. Nrf2 and its role in MANF-mediated degradation may provide new sights that target degradation pathways to counteract SNCA pathology in PD.

Dynamic muscle paralytic effects of a novel botulinum toxin A free of neurotoxin-associated proteins.

Structurally, botulinum toxin type A (BTX-A) is composed of neurotoxin and nontoxic complexing proteins (CPs), and the neurotoxin has the function of blocking acetylcholine release from the neuromuscular junction and therefore paralyzing muscles. Nowadays, a novel botulinum toxin A free of CPs (chinbotulinumtoxin A, A/Chin) is produced, and the present study comprehensively evaluated the dynamic paralytic effect of A/Chin on the gastrocnemius muscle of rats. Different doses (0.01, 0.1, 0.5, 1, 2, and 4 U) of A/Chin and other BTX-As with and without CPs were administered to the gastrocnemius muscles of rats and muscle strength was measured and compared at different postinjection timepoints (from day 0 to 84). With the dose increased, time-to-peak paralytic effect of other BTX-As varied from day 3 to day 14, while A/Chin groups showed rapid and steady time to peak on day 3. At the lowest dose of 0.01 U, A/Chin showed significantly better peak paralytic effect than the others on day 3. When the dose increased to 0.5 U and more, A/Chin group also showed significant paralytic effect when the paralytic effect of other BTX-As was worn off. Moreover, the paralytic effect of A/Chin was confirmed as muscle atrophy while hematoxylin-eosin staining was performed. In conclusion, compared with other BTX-As, A/Chin showed rapid and steady time-to-peak paralytic effect and long-term paralytic efficacy at the same dose level. And it might lay a solid foundation for further wide application of A/Chin in both clinical and cosmetic areas.