BACKGROUND Autosomal recessive spinocerebellar ataxia type 4(SCAR4)is a type of SCA that is a group of hereditary diseases characterized by gait ataxia.The main clinical features of SCAR4 are progressive cerebellar at...BACKGROUND Autosomal recessive spinocerebellar ataxia type 4(SCAR4)is a type of SCA that is a group of hereditary diseases characterized by gait ataxia.The main clinical features of SCAR4 are progressive cerebellar ataxia,pyramidal signs,neuropathy,and macrosaccadic intrusions.To date,many gene dysfunctions have been reported to be associated with SCAR4.CASE SUMMARY Here,we report a novel compound heterozygous mutation,c.3288delA(p.Asp1097-ThrfsTer6),in the VPS13D gene in a young female Chinese patient.The patient found something wrong with her legs about 10 years ago and presented with the typical characteristics of SCAR4 when she came to the hospital,including ataxia,neuropathy,and positive pyramidal signs.She was then diagnosed with SCAR4 and went home with symptomatic schemes.CONCLUSION SCAR4 is a hereditary disease characterized by ataxia,pyramidal signs,neuropathy,and macrosaccadic intrusions.We report a novel compound heterozygous mutation,c.3288delA(p.Asp1097ThrfsTer6),in the VPS13D gene,which enriches the gene mutation spectrum and provides additional information about SCAR4.展开更多
Abnormal mitochondrial dynamics can lead to seizures,and improved mitochon-drial dynamics can alleviate seizures.Vacuolar protein sorting 13D(VPS13D)is closely associ-ated with regulating mitochondrial homeostasis and...Abnormal mitochondrial dynamics can lead to seizures,and improved mitochon-drial dynamics can alleviate seizures.Vacuolar protein sorting 13D(VPS13D)is closely associ-ated with regulating mitochondrial homeostasis and autophagy.However,further investigation is required to determine whether VPS13D affects seizures by influencing mitochondrial dy-namics and autophagy.We aimed to investigate the influence of VPS13D on behavior in a rat model of acute epileptic seizures.Hence,we established an acute epileptic seizure rat model and employed the CRISPR/CAS9 technology to construct a lentivirus to silence the Vps13d gene.Furthermore,we used the HT22 mouse hippocampal neuron cell line to establish a stable strain with suppressed expression of Vps13d in vitro.Then,we performed quantitative prote-omic and bioinformatics analyses to confirm the mechanism by which VPS13D influences mito-chondrial dynamics and autophagy,both in vitro and in vivo using the experimental acute epileptic seizure model.We found that knockdown of Vps13d resulted in reduced seizure la-tency and increased seizure frequency in the experimental rats.Immunofluorescence staining and western blot analysis revealed a significant increase in mitochondrial dynamin-related pro-tein 1 expression following Vps13d knockdown.Moreover,we observed a significant reduction in LC3Il protein expression levels and the LC31/LC3l ratio(indicators for autophagy)accompa-nied by a significant increase in P62 expression(an autophagy adaptor protein).The proteomic analysis confirmed the up-regulation of P62 protein expression.Therefore,we propose that VPS13D plays a role in modulating seizures by influencing mitochondrial dynamics and autophagy.展开更多
文摘BACKGROUND Autosomal recessive spinocerebellar ataxia type 4(SCAR4)is a type of SCA that is a group of hereditary diseases characterized by gait ataxia.The main clinical features of SCAR4 are progressive cerebellar ataxia,pyramidal signs,neuropathy,and macrosaccadic intrusions.To date,many gene dysfunctions have been reported to be associated with SCAR4.CASE SUMMARY Here,we report a novel compound heterozygous mutation,c.3288delA(p.Asp1097-ThrfsTer6),in the VPS13D gene in a young female Chinese patient.The patient found something wrong with her legs about 10 years ago and presented with the typical characteristics of SCAR4 when she came to the hospital,including ataxia,neuropathy,and positive pyramidal signs.She was then diagnosed with SCAR4 and went home with symptomatic schemes.CONCLUSION SCAR4 is a hereditary disease characterized by ataxia,pyramidal signs,neuropathy,and macrosaccadic intrusions.We report a novel compound heterozygous mutation,c.3288delA(p.Asp1097ThrfsTer6),in the VPS13D gene,which enriches the gene mutation spectrum and provides additional information about SCAR4.
基金supported by the Science and Technology Fund Project of the Guizhou Provincial Health Commission (China) (No.gzwkj2023-109,gzwkj2021.017,gzwjkj2020-1-010)the Science and Technology Plan Project of Zunyi City,Guizhou,China (No.ZSKHZC-HZ (2020)172)+1 种基金the Science and Technology Project in Guizhou Province,China (No.QKHJC-ZK[2021]NO.408)the National Natural Science Foundation of China (No.82101527).
文摘Abnormal mitochondrial dynamics can lead to seizures,and improved mitochon-drial dynamics can alleviate seizures.Vacuolar protein sorting 13D(VPS13D)is closely associ-ated with regulating mitochondrial homeostasis and autophagy.However,further investigation is required to determine whether VPS13D affects seizures by influencing mitochondrial dy-namics and autophagy.We aimed to investigate the influence of VPS13D on behavior in a rat model of acute epileptic seizures.Hence,we established an acute epileptic seizure rat model and employed the CRISPR/CAS9 technology to construct a lentivirus to silence the Vps13d gene.Furthermore,we used the HT22 mouse hippocampal neuron cell line to establish a stable strain with suppressed expression of Vps13d in vitro.Then,we performed quantitative prote-omic and bioinformatics analyses to confirm the mechanism by which VPS13D influences mito-chondrial dynamics and autophagy,both in vitro and in vivo using the experimental acute epileptic seizure model.We found that knockdown of Vps13d resulted in reduced seizure la-tency and increased seizure frequency in the experimental rats.Immunofluorescence staining and western blot analysis revealed a significant increase in mitochondrial dynamin-related pro-tein 1 expression following Vps13d knockdown.Moreover,we observed a significant reduction in LC3Il protein expression levels and the LC31/LC3l ratio(indicators for autophagy)accompa-nied by a significant increase in P62 expression(an autophagy adaptor protein).The proteomic analysis confirmed the up-regulation of P62 protein expression.Therefore,we propose that VPS13D plays a role in modulating seizures by influencing mitochondrial dynamics and autophagy.
