脊髓小脑性共济失调17型(spinocerebellar ataxia type 17,SCA17)是一种罕见的常染色体显性遗传病,由位于6q27染色体上的TATA box结合蛋白基因(TBP)异常胞嘧啶-腺嘌呤-腺嘌呤/胞嘧啶-腺嘌呤-鸟嘌呤(cytosine-adenine-adenine/cytosine-a...脊髓小脑性共济失调17型(spinocerebellar ataxia type 17,SCA17)是一种罕见的常染色体显性遗传病,由位于6q27染色体上的TATA box结合蛋白基因(TBP)异常胞嘧啶-腺嘌呤-腺嘌呤/胞嘧啶-腺嘌呤-鸟嘌呤(cytosine-adenine-adenine/cytosine-adenineguanine,CAA/CAG)重复扩增引起[1]。该病的临床表现具有高度异质性,除了具有脊髓小脑共济失调(spinocerebellar ataxias,SCAs)典型的共济失调和构音障碍外,还可表现为痴呆、精神症状或舞蹈样不自主运动。目前其临床诊断主要依靠典型的临床表现、遗传家族史、特征性生化指标异常、遗传性共济失调相关神经影像学及电生理检查和基因检测。展开更多
目的探讨脊髓小脑性共济失调3型(spinocerebellar ataxia type 3,SCA3)患者体质量指数(body mass index,BMI)与疾病严重程度的相关关系。方法选择2022年7月—2023年8月福建医科大学附属第一医院神经内科确诊为SCA3的患者作为病例组,2024...目的探讨脊髓小脑性共济失调3型(spinocerebellar ataxia type 3,SCA3)患者体质量指数(body mass index,BMI)与疾病严重程度的相关关系。方法选择2022年7月—2023年8月福建医科大学附属第一医院神经内科确诊为SCA3的患者作为病例组,2024年6月—2024年10月的健康个体作为对照组。比较两组的BMI。收集患者人口统计学及临床统计学资料,采用共济失调等级量表评估SCA3患者共济失调的严重程度,并评估BMI与疾病严重程度的关系。结果共纳入患者101例,健康个体101例。SCA3患者较正常对照人群BMI水平降低(t=-2.370,P=0.019)。多重线性回归分析结果显示,BMI、病程和吸烟史对SCA3患者疾病严重程度有影响(P<0.05),病程和疾病严重程度对SCA3患者疾病进展有影响(P<0.05)。结论SCA3患者BMI与疾病严重程度存在相关性,通过控制BMI水平可能有助于SCA3患者的病情控制。展开更多
Spinocerebellar ataxia(SCA)type 51 is a neurodegenerative disease caused by CAG repeat expansions in exon 1 of the THAP11 gene.These repeats are translated into a glutamine-rich protein,THAP11-polyQ,which forms protei...Spinocerebellar ataxia(SCA)type 51 is a neurodegenerative disease caused by CAG repeat expansions in exon 1 of the THAP11 gene.These repeats are translated into a glutamine-rich protein,THAP11-polyQ,which forms protein aggregates and exhibits toxicity in cell models;however,the underlying mechanism remains unclear.In this study,we generate transgenic Drosophila models expressing varying lengths of THAP11-polyQ using the UAS-GAL4 system and assess neurodegeneration through pathological and behavioral analyses.Our results demonstrate that expression of THAP11-polyQ in transgenic flies leads to progressive neuronal cell loss,locomotor deficiency,and reduced survival.RNA sequencing of patient-derived skin fibroblasts reveals significant enrichment of the PI3K–Akt–mTOR pathway,and electron microscopy of transgenic flies shows an increase in multilamellar bodies,suggesting involvement of autophagy in SCA51.Consequently,we treat the fly model with rapamycin,an mTOR inhibitor known to enhance autophagy.This treatment reduces toxic THAP11-polyQ protein aggregates,significantly alleviates neuronal degeneration,and improves locomotor function,consistent with the rescue effects observed upon overexpression of Atg8a.Overall,these findings suggest that the Drosophila model,which recapitulates the neurodegenerative features of SCA51,can be used to investigate pathogenic mechanisms and that rapamycin holds promising potential as a therapeutic approach for this disease.展开更多
文摘目的探讨脊髓小脑性共济失调3型(spinocerebellar ataxia type 3,SCA3)患者体质量指数(body mass index,BMI)与疾病严重程度的相关关系。方法选择2022年7月—2023年8月福建医科大学附属第一医院神经内科确诊为SCA3的患者作为病例组,2024年6月—2024年10月的健康个体作为对照组。比较两组的BMI。收集患者人口统计学及临床统计学资料,采用共济失调等级量表评估SCA3患者共济失调的严重程度,并评估BMI与疾病严重程度的关系。结果共纳入患者101例,健康个体101例。SCA3患者较正常对照人群BMI水平降低(t=-2.370,P=0.019)。多重线性回归分析结果显示,BMI、病程和吸烟史对SCA3患者疾病严重程度有影响(P<0.05),病程和疾病严重程度对SCA3患者疾病进展有影响(P<0.05)。结论SCA3患者BMI与疾病严重程度存在相关性,通过控制BMI水平可能有助于SCA3患者的病情控制。
基金financially supported by the National Natural Science Foundation of China(82402177,82171846,82422025,82471430)Clinical Medicine Plus X-Young Scholars Project of Peking University(PKU2025PKULCXQ026)+1 种基金National High Level Hospital Clinical Research Funding(Interdepartmental Research Project of Peking University First Hospital,2023IR51,High Quality Clinical Research Project of Peking University First Hospital,2022CR69)Beijing Key Laboratory of Molecular Diagnosis and Study on Pediatric Genetic Diseases(BZ0317).
文摘Spinocerebellar ataxia(SCA)type 51 is a neurodegenerative disease caused by CAG repeat expansions in exon 1 of the THAP11 gene.These repeats are translated into a glutamine-rich protein,THAP11-polyQ,which forms protein aggregates and exhibits toxicity in cell models;however,the underlying mechanism remains unclear.In this study,we generate transgenic Drosophila models expressing varying lengths of THAP11-polyQ using the UAS-GAL4 system and assess neurodegeneration through pathological and behavioral analyses.Our results demonstrate that expression of THAP11-polyQ in transgenic flies leads to progressive neuronal cell loss,locomotor deficiency,and reduced survival.RNA sequencing of patient-derived skin fibroblasts reveals significant enrichment of the PI3K–Akt–mTOR pathway,and electron microscopy of transgenic flies shows an increase in multilamellar bodies,suggesting involvement of autophagy in SCA51.Consequently,we treat the fly model with rapamycin,an mTOR inhibitor known to enhance autophagy.This treatment reduces toxic THAP11-polyQ protein aggregates,significantly alleviates neuronal degeneration,and improves locomotor function,consistent with the rescue effects observed upon overexpression of Atg8a.Overall,these findings suggest that the Drosophila model,which recapitulates the neurodegenerative features of SCA51,can be used to investigate pathogenic mechanisms and that rapamycin holds promising potential as a therapeutic approach for this disease.
