The regulation of mRNA localization and local translation play vital roles in the maintenance of cellular structure and function.Many human neurodegenerative diseases,such as fragile X syndrome,amyotrophic lateral scl...The regulation of mRNA localization and local translation play vital roles in the maintenance of cellular structure and function.Many human neurodegenerative diseases,such as fragile X syndrome,amyotrophic lateral sclerosis,Alzheimer’s disease,and spinal muscular atrophy,have been characterized by pathological changes in neuronal axons,including abnormal mRNA translation,the loss of protein expression,or abnormal axon transport.Moreover,the same protein and mRNA molecules have been associated with variable functions in different diseases due to differences in their interaction networks.In this review,we briefly examine fragile X syndrome,amyotrophic lateral sclerosis,Alzheimer’s disease,and spinal muscular atrophy,with a focus on disease pathogenesis with regard to local mRNA translation and axon transport,suggesting possible treatment directions.展开更多
Background： Amyotrophic lateral sclerosis （ALS） and some mimic disorders, such as distal-type cervical spondylotic amyotrophy （LISA）, Hirayama disease （HD）, and spinobulbar muscular atrophy （SBMA） may present...Background： Amyotrophic lateral sclerosis （ALS） and some mimic disorders, such as distal-type cervical spondylotic amyotrophy （LISA）, Hirayama disease （HD）, and spinobulbar muscular atrophy （SBMA） may present with intrinsic hand muscle atrophy. This study aimed to investigate different patterns of small hand muscle involvement in ALS and some mimic disorders. Methods： We compared the abductor digiti minimi/abductor pollicis brevis （ADM/APB） compound muscle action potential （（＇MAP） ratios between 200 ALS patients, 95 patients with distal-type CSA, 88 HD patients, 43 SBMA patients, and 150 normal controls. Results： The ADM/APB （？MAP amplitude ratio was significantly higher in the ALS patients （P 〈 0.001） than that in the normal controls. The ADM/APB CMAP amplitude ratio was significantly reduced in the patients with distal-type CSA （P 〈 0,001 ） and the H I） patients （P 〈 0.001 ） compared with that in the normal controls. The patients with distal-type CSA had significantly lower APB CMAP amplitude than the HD patients （P- 0.004）. The ADM/APB CMAP amplitude ratio was significantly lower in the HD patients （P 〈 0.001 ） than that in the patients with distal-type CSA. The ADM/APB CMAP amplitude ratio of the SBMA patients was similar to that of the normal controls （P = 0.862）. An absent APB CMAP and an abnormally high ADM/APB CMAP amplitude ratio （_〉4.5） were observed exclusively in the ALS patients. Conclusions： The different patterns of small hand muscle atrophy between the ALS patients and the patients with mimic disorders presumably reflect distinct pathophysiological mechanisms underlying different disorders, and may aid in distinguishing between ALS and mimic disorders.展开更多
Common neurodegenerative diseases of the central nervous system are characterized by progressive damage to the function of neurons, even leading to the permanent loss of function. Gene therapy via gene replacement or ...Common neurodegenerative diseases of the central nervous system are characterized by progressive damage to the function of neurons, even leading to the permanent loss of function. Gene therapy via gene replacement or gene correction provides the potential for transformative therapies to delay or possibly stop further progression of the neurodegenerative disease in affected patients. Adeno-associated virus has been the vector of choice in recent clinical trials of therapies for neurodegenerative diseases due to its safety and efficiency in mediating gene transfer to the central nervous system. This review aims to discuss and summarize the progress and clinical applications of adeno-associated virus in neurodegenerative disease in central nervous system. Results from some clinical trials and successful cases of central neurodegenerative diseases deserve further study and exploration.展开更多
Autophagy is the main catabolic pathway in cells for the degradation of impaired proteins and organelles. Accumulating evidence supports the hypothesis that dysfunction of autophagy, leading to an imbalance of proteos...Autophagy is the main catabolic pathway in cells for the degradation of impaired proteins and organelles. Accumulating evidence supports the hypothesis that dysfunction of autophagy, leading to an imbalance of proteostasis and the accumulation of toxic proteins in neurons, is a central player in the pathogenesis of neurodegenerative diseases such as Alzheimer＇s disease, Parkinson＇s disease, and amyotrophic lateral sclerosis （ALS）. The clinical pathology of ALS is complex and many genes associated with autophagy and RNA processing are mutated in patients with the familial form. But a causal relationship between autophagic dysfunction and ALS has not been fully established. More importantly, studies on the pathological mechanism of ALS are mainly based on animal models that may not precisely recapitulate the disease itself in human beings. The development of human iPSC techniques allows us to address these issues directly in human cell models that may profoundly influence drug discovery for ALS.展开更多
基金This work was supported by the National Natural Science Foundation of China,Nos.81830036(to GC),81771255(to GC),81771254(to HYL),81971106(to ZQY)Project of Jiangsu Provincial Medical Innovation Team,No.CXTDA2017003(to GC)+2 种基金Jiangsu Provincial Medical Youth Talent,No.QNRC2016728(to HYL)the Natural Science Foundation of Jiangsu Province,No.BK20170363(to HYL)Gusu Health Personnel Training Project,No.GSWS2019030(to HYL)。
文摘The regulation of mRNA localization and local translation play vital roles in the maintenance of cellular structure and function.Many human neurodegenerative diseases,such as fragile X syndrome,amyotrophic lateral sclerosis,Alzheimer’s disease,and spinal muscular atrophy,have been characterized by pathological changes in neuronal axons,including abnormal mRNA translation,the loss of protein expression,or abnormal axon transport.Moreover,the same protein and mRNA molecules have been associated with variable functions in different diseases due to differences in their interaction networks.In this review,we briefly examine fragile X syndrome,amyotrophic lateral sclerosis,Alzheimer’s disease,and spinal muscular atrophy,with a focus on disease pathogenesis with regard to local mRNA translation and axon transport,suggesting possible treatment directions.
文摘Background： Amyotrophic lateral sclerosis （ALS） and some mimic disorders, such as distal-type cervical spondylotic amyotrophy （LISA）, Hirayama disease （HD）, and spinobulbar muscular atrophy （SBMA） may present with intrinsic hand muscle atrophy. This study aimed to investigate different patterns of small hand muscle involvement in ALS and some mimic disorders. Methods： We compared the abductor digiti minimi/abductor pollicis brevis （ADM/APB） compound muscle action potential （（＇MAP） ratios between 200 ALS patients, 95 patients with distal-type CSA, 88 HD patients, 43 SBMA patients, and 150 normal controls. Results： The ADM/APB （？MAP amplitude ratio was significantly higher in the ALS patients （P 〈 0.001） than that in the normal controls. The ADM/APB CMAP amplitude ratio was significantly reduced in the patients with distal-type CSA （P 〈 0,001 ） and the H I） patients （P 〈 0.001 ） compared with that in the normal controls. The patients with distal-type CSA had significantly lower APB CMAP amplitude than the HD patients （P- 0.004）. The ADM/APB CMAP amplitude ratio was significantly lower in the HD patients （P 〈 0.001 ） than that in the patients with distal-type CSA. The ADM/APB CMAP amplitude ratio of the SBMA patients was similar to that of the normal controls （P = 0.862）. An absent APB CMAP and an abnormally high ADM/APB CMAP amplitude ratio （_〉4.5） were observed exclusively in the ALS patients. Conclusions： The different patterns of small hand muscle atrophy between the ALS patients and the patients with mimic disorders presumably reflect distinct pathophysiological mechanisms underlying different disorders, and may aid in distinguishing between ALS and mimic disorders.
文摘Common neurodegenerative diseases of the central nervous system are characterized by progressive damage to the function of neurons, even leading to the permanent loss of function. Gene therapy via gene replacement or gene correction provides the potential for transformative therapies to delay or possibly stop further progression of the neurodegenerative disease in affected patients. Adeno-associated virus has been the vector of choice in recent clinical trials of therapies for neurodegenerative diseases due to its safety and efficiency in mediating gene transfer to the central nervous system. This review aims to discuss and summarize the progress and clinical applications of adeno-associated virus in neurodegenerative disease in central nervous system. Results from some clinical trials and successful cases of central neurodegenerative diseases deserve further study and exploration.
基金supported by the Ministry of Science and Technology of China (2011CB966200)the National Natural Science Foundation of China (81401053,31471029,81461138037,and 81472141)+2 种基金the National Program for Support of Top-notch Young Professionalsthe Program for Young Excellent Talents in Tongji University (2014KJ049)the Public Health Bureau of Tianjin Municipality,China (13KG127)
文摘Autophagy is the main catabolic pathway in cells for the degradation of impaired proteins and organelles. Accumulating evidence supports the hypothesis that dysfunction of autophagy, leading to an imbalance of proteostasis and the accumulation of toxic proteins in neurons, is a central player in the pathogenesis of neurodegenerative diseases such as Alzheimer＇s disease, Parkinson＇s disease, and amyotrophic lateral sclerosis （ALS）. The clinical pathology of ALS is complex and many genes associated with autophagy and RNA processing are mutated in patients with the familial form. But a causal relationship between autophagic dysfunction and ALS has not been fully established. More importantly, studies on the pathological mechanism of ALS are mainly based on animal models that may not precisely recapitulate the disease itself in human beings. The development of human iPSC techniques allows us to address these issues directly in human cell models that may profoundly influence drug discovery for ALS.
