Translational Neurobiology. Current Challenges and Opportunities

（中文介绍）转化神经生物学是整合从神经生物学的基础研究到优化人类神经系统疾病病人的护理和预防战略，从实验室到临床的研究。在过去10年药物的发现已经有了革命性的变化。然而，新药品审批的数量仍然停滞不前，药物市场的成本比以往任何时候都高。这也提出现有药物开发的模式，已不适应变化的科学和公众对制药公司的期待。

S1B-2 Therapeutics and Biomarker Development in Huntington’Disease

Most neurodegenerative diseases,including Alzheimer’s,Parkinson’s,and Huntington’s disease(HD),have converging pathogenesis,such as formation of abnormal protein aggregates and mitochondrial dysfunction.Unfortunately,despite tremendous efforts by many scientists and increasing knowledge about disease mechanisms,we still lack disease-modifying treatments for any of these diseases.Drug discovery has been revolutionized in the past decade.Despite technological advances as a result of substantial investment,the number of new drug approvals remains stagnant and the cost of bringing a drug to market is higher than ever.This highlights the persistence of a model of drug development that has not adapted to changes in science and public perception of drug companies.While these diseases affect different areas of the brain and are distinct at the cellular and molecular levels,they share many underlying similarities.Thus,development of treatment for any of these diseases may provide clues to accelerate the path to the treatment for other neurodegenerative diseases.Research into potential therapies for HD is particularly attractive because it is a genetically homogeneous disease for which well-established models exist.The HD gene encodes the protein huntingtin(Htt),whose polyglutamine expansion is believed to mediate the cytotoxic effects of HD.Therefore,HD also serves a model for polyglutamine diseases.HD is a monogenic neurodegenerative disorder caused by mutation of the gene Huntingtin.Htt lowering(gene silencing)strategies,including antisense oligonucleotides,shRNA,miRNA et al,have shown great preclinical promise,and the first HTT lowering clinical trial is underway.The key to success of these trials will be to know where and when to intervene,since these reagents do not penetrate the blood-brain-barrier,and must be delivered directly to the CNS.HD is notable for preferential atrophy of the striatum but also involves degeneration in cortex,subcortical white matter,and specific subcortical grey matter regions.It has been shown regional spread of pathology in the HD brain using neuroimaging.In addition,neurodegeneration in HD is mainly caused by toxic effects of the abnormal Htt protein,and there is increasing evidence that mutant Htt can spread,like prions.A better understanding of HD pathology at a cellular level and in the network context would be important for determining the optimal timing and brain regional location of therapeutic interventions.HD mouse models provide unique values to answer these questions,as brain samples can be collected at a temporal manner from different disease stages(before disease onset,at the onset,after the onset)in a relatively short period.Knowledge of HD pathogenesis is bearing fruit in experimental treatments,using agents to decrease production of the huntingtin message RNA and protein.An understanding of how pathology of HD may spread throughout the brain can be guided by an understanding of the cortico-basal-ganglionic circuitry.Selective pathology within the basal ganglia circuit may contribute to features of HD phenotype.

Mononuclear cell therapy of neonatal hypoxic-ischemic encephalopathy in preclinical versus clinical studies:A systematic analysis of therapeutic efficacy and study design

Background:Hypoxic-ischemic encephalopathy(HIE)is a devastating condition affecting around 8.5 in 1000 newborns globally.Therapeutic hypothermia(TH)can reduce mortality and,to a limited extent,disability after HIE.Nevertheless,there is a need for new and effective treatment strategies.Cell-based treatments using mononuclear cells(MNCs),which can be sourced from umbilical cord blood,are currently being investigated.Despite promising preclinical results,there is currently no strong indicator for the clinical efficacy of the approach.This analysis aimed to provide potential explanations for this discrepancy.Methods:A systematic review and meta-analysis were conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines.Preclinical and clinical studies were retrieved from PubMed,Web of Science,Scopus,and clinicaltrials.gov using a predefined search strategy.A total of 17 preclinical and 7 clinical studies were included.We analyzed overall MNC efficacy in preclinical trials,the methodological quality of preclinical trials,and relevant design features in preclinical versus clinical trials.Results:There was evidence for MNC therapeutic efficacy in preclinical models of HIE.The methodological quality of preclinical studies was not optimal,and statistical design quality was particularly poor.However,methodological quality was above the standard in other fields.There were significant differences in preclinical versus clinical study design including the use of TH as a baseline treatment(only in clinical studies)and much higher MNC doses being applied in preclinical studies.Conclusions:Based on the analyzed data,it is unlikely that therapeutic effect size is massively overestimated in preclinical studies.It is more plausible that the many design differences between preclinical and clinical trials are responsible for the so far lacking proof of the efficacy of MNC treatments in HIE.Additional preclinical and clinical research is required to optimize the application of MNC for experimental HIE treatment.

Unraveling the mechanisms of synapse formation and axon regeneration: the awesome power of C. elegans genetics

Since Caenorhabditis elegans was chosen as a model organism by Sydney Brenner in 1960's, genetic studies in this organism have been instrumental in discovering the function of genes and in deciphering molecular signaling network. The small size of the organism and the simple nervous system enable the complete reconstruction of the first connectome. The stereotypic developmental program and the anatomical reproducibility of synaptic connections provide a blueprint to dissect the mechanisms underlying synapse formation. Recent technological innovation using laser surgery of single axons and in vivo imaging has also made C. elegans a new model for axon regeneration. Importantly, genes regulating synaptogenesis and axon regeneration are highly conserved in function across animal phyla. This mini-review will summarize the main approaches and the key findings in understanding the mechanisms underlying the development and maintenance of the nervous system. The impact of such findings underscores the awesome power of C. elegans genetics.

Erratum to: Unraveling the mechanisms of synapse formation and axon regeneration: the awesome power of C. elegans genetics

Erratum to:SCIENCE CHINA Life Sciences,November 2015 Vol.58 No.11:1084–1088doi:10.1007/s11427-015-4962-9In the first paragraph of the manuscript,the name of Charles Harrington was printed in error,should be Charles Sherrington.

Highlights of the 2nd International Symposium on Tribbles and Diseases: tribbles tremble in therapeutics for immunity, metabolism, fundamental cell biology and cancer

The Tribbles(TRIB) family of pseudokinase proteins has been shown to play key roles in cell cycle, metabolic diseases, chronic inflammatory disease, and cancer development. A better understanding of the mechanisms of TRIB pseudokinases could provide new insights for disease development and help promote TRIB proteins as novel therapeutic targets for drug discovery. At the 2 nd International Symposium on Tribbles and Diseases held on May 7–9, 2018 in Beijing, China, a group of leading Tribbles scientists reported their findings and ongoing studies about the effects of the different TRIB proteins in the areas of immunity, metabolism, fundamental cell biology and cancer. Here, we summarize important and insightful overviews from 4 keynote lectures, 13 plenary lectures and 8 short talks that took place during this meeting. These findings may offer new insights for the understanding of the roles of TRIB pseudokinases in the development of various diseases.