文献检索文档翻译深度研究
Suppr Zotero 插件Zotero 插件
邀请有礼套餐&价格历史记录

新学期,新优惠

限时优惠:9月1日-9月22日

30天高级会员仅需29元

1天体验卡首发特惠仅需5.99元

了解详情
不再提醒
插件&应用
Suppr Zotero 插件Zotero 插件浏览器插件Mac 客户端Windows 客户端微信小程序
高级版
套餐订阅购买积分包
AI 工具
文献检索文档翻译深度研究
关于我们
关于 Suppr公司介绍联系我们用户协议隐私条款
关注我们

Suppr 超能文献

核心技术专利:CN118964589B侵权必究
粤ICP备2023148730 号-1Suppr @ 2025

从亨廷顿舞蹈症患者成纤维细胞直接转化而来的纹状体神经元重现了与年龄相关的疾病表型。

Striatal neurons directly converted from Huntington's disease patient fibroblasts recapitulate age-associated disease phenotypes.

作者信息

Victor Matheus B, Richner Michelle, Olsen Hannah E, Lee Seong Won, Monteys Alejandro M, Ma Chunyu, Huh Christine J, Zhang Bo, Davidson Beverly L, Yang X William, Yoo Andrew S

机构信息

Department of Developmental Biology, Center for Regenerative Medicine, Washington University School of Medicine, St. Louis, MO, USA.

Graduate Program in Neuroscience, Division of Biology and Biomedical Sciences, Washington University School of Medicine, St. Louis, MO, USA.

出版信息

Nat Neurosci. 2018 Mar;21(3):341-352. doi: 10.1038/s41593-018-0075-7. Epub 2018 Feb 5.


DOI:10.1038/s41593-018-0075-7
PMID:29403030
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5857213/
Abstract

In Huntington's disease (HD), expansion of CAG codons in the huntingtin gene (HTT) leads to the aberrant formation of protein aggregates and the differential degeneration of striatal medium spiny neurons (MSNs). Modeling HD using patient-specific MSNs has been challenging, as neurons differentiated from induced pluripotent stem cells are free of aggregates and lack an overt cell death phenotype. Here we generated MSNs from HD patient fibroblasts through microRNA-based direct neuronal conversion, bypassing the induction of pluripotency and retaining age signatures of the original fibroblasts. We found that patient MSNs consistently exhibited mutant HTT (mHTT) aggregates, mHTT-dependent DNA damage, mitochondrial dysfunction and spontaneous degeneration in culture over time. We further provide evidence that erasure of age stored in starting fibroblasts or neuronal conversion of presymptomatic HD patient fibroblasts results in differential manifestation of cellular phenotypes associated with HD, highlighting the importance of age in modeling late-onset neurological disorders.

摘要

在亨廷顿舞蹈病(HD)中,亨廷顿蛋白基因(HTT)中CAG密码子的扩增会导致蛋白质聚集体异常形成以及纹状体中等棘状神经元(MSN)的差异性退化。使用患者特异性MSN对HD进行建模一直具有挑战性,因为从诱导多能干细胞分化而来的神经元没有聚集体,并且缺乏明显的细胞死亡表型。在这里,我们通过基于微小RNA的直接神经元转化,从HD患者成纤维细胞生成了MSN,绕过了多能性诱导并保留了原始成纤维细胞的年龄特征。我们发现,患者MSN在培养过程中始终表现出突变型HTT(mHTT)聚集体、mHTT依赖性DNA损伤、线粒体功能障碍和自发性退化。我们进一步提供证据表明,消除起始成纤维细胞中存储的年龄或对症状前HD患者成纤维细胞进行神经元转化会导致与HD相关的细胞表型的不同表现,突出了年龄在模拟迟发性神经疾病中的重要性。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d52e/5857213/7b6b32c5c4d0/nihms931205f8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d52e/5857213/cd028bbb5c1d/nihms931205f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d52e/5857213/47080d984e50/nihms931205f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d52e/5857213/7e803754be61/nihms931205f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d52e/5857213/8e7924a819c8/nihms931205f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d52e/5857213/0e23e8ff75a5/nihms931205f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d52e/5857213/461758c3b7da/nihms931205f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d52e/5857213/feb1fc256f24/nihms931205f7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d52e/5857213/7b6b32c5c4d0/nihms931205f8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d52e/5857213/cd028bbb5c1d/nihms931205f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d52e/5857213/47080d984e50/nihms931205f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d52e/5857213/7e803754be61/nihms931205f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d52e/5857213/8e7924a819c8/nihms931205f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d52e/5857213/0e23e8ff75a5/nihms931205f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d52e/5857213/461758c3b7da/nihms931205f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d52e/5857213/feb1fc256f24/nihms931205f7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d52e/5857213/7b6b32c5c4d0/nihms931205f8.jpg

相似文献

[1]
Striatal neurons directly converted from Huntington's disease patient fibroblasts recapitulate age-associated disease phenotypes.

Nat Neurosci. 2018-3

[2]
Patient-derived neuron model: Capturing age-dependent adult-onset degenerative pathology in Huntington's disease.

Mol Cells. 2024-4

[3]
Full length mutant huntingtin is required for altered Ca2+ signaling and apoptosis of striatal neurons in the YAC mouse model of Huntington's disease.

Neurobiol Dis. 2008-7

[4]
Non-Cell Autonomous and Epigenetic Mechanisms of Huntington's Disease.

Int J Mol Sci. 2021-11-19

[5]
Msh2 acts in medium-spiny striatal neurons as an enhancer of CAG instability and mutant huntingtin phenotypes in Huntington's disease knock-in mice.

PLoS One. 2012-9-7

[6]
Differential changes to D1 and D2 medium spiny neurons in the 12-month-old Q175+/- mouse model of Huntington's Disease.

PLoS One. 2018-8-17

[7]
Dermal Fibroblast Cell Line from a Patient with the Huntington's Disease as a Promising Model for Studying Disease Pathogenesis: Production and Characterization.

Biochemistry (Mosc). 2024-7

[8]
Structural and functional features of medium spiny neurons in the BACHDΔN17 mouse model of Huntington's Disease.

PLoS One. 2020-6-23

[9]
Modeling Huntington disease through microRNA-mediated neuronal reprogramming identifies age-associated autophagy dysfunction driving the onset of neurodegeneration.

Autophagy. 2023-9

[10]
Gedunin Degrades Aggregates of Mutant Huntingtin Protein and Intranuclear Inclusions via the Proteasomal Pathway in Neurons and Fibroblasts from Patients with Huntington's Disease.

Neurosci Bull. 2019-8-20

引用本文的文献

[1]
Cellular Models of Aging and Senescence.

Cells. 2025-8-18

[2]
RNA triggers chronic stress during neuronal aging.

bioRxiv. 2025-8-5

[3]
The complex web of membrane contact sites in brain aging and neurodegeneration.

Cell Mol Life Sci. 2025-8-8

[4]
Durable silencing using non-evolved dCas9 epigenome editors in patient-derived cells.

Mol Ther Nucleic Acids. 2025-5-14

[5]
Three-dimensional cell-cell interactions promote direct reprogramming of patient fibroblasts into functional and transplantable neurons.

Sci Adv. 2025-6-6

[6]
Neuronal aging causes mislocalization of splicing proteins and unchecked cellular stress.

Nat Neurosci. 2025-6

[7]
Tracing mitochondrial marks of neuronal aging in iPSCs-derived neurons and directly converted neurons.

Commun Biol. 2025-5-10

[8]
Mitochondrial DNA editing: Key to the treatment of neurodegenerative diseases.

Genes Dis. 2024-9-21

[9]
Somatic and Stem Cell Bank to study the contribution of African ancestry to dementia: African iPSC Initiative.

Alzheimers Dement. 2025-4

[10]
An accelerated human in-vitro aging model mimicsin-vivo aging and facilitates dynamic testing of anti-aging compounds.

Res Sq. 2025-3-28

本文引用的文献

[1]
MicroRNAs Induce a Permissive Chromatin Environment that Enables Neuronal Subtype-Specific Reprogramming of Adult Human Fibroblasts.

Cell Stem Cell. 2017-9-7

[2]
Abnormal degradation of the neuronal stress-protective transcription factor HSF1 in Huntington's disease.

Nat Commun. 2017-2-13

[3]
Oxidative Stress and Huntington's Disease: The Good, The Bad, and The Ugly.

J Huntingtons Dis. 2016-10-1

[4]
Maintenance of age in human neurons generated by microRNA-based neuronal conversion of fibroblasts.

Elife. 2016-9-20

[5]
The Zinc Finger Transcription Factor Sp9 Is Required for the Development of Striatopallidal Projection Neurons.

Cell Rep. 2016-8-2

[6]
Manifestation of Huntington's disease pathology in human induced pluripotent stem cell-derived neurons.

Mol Neurodegener. 2016-4-14

[7]
Directly Reprogrammed Human Neurons Retain Aging-Associated Transcriptomic Signatures and Reveal Age-Related Nucleocytoplasmic Defects.

Cell Stem Cell. 2015-12-3

[8]
MicroRNA-based conversion of human fibroblasts into striatal medium spiny neurons.

Nat Protoc. 2015-9-17

[9]
Activin A directs striatal projection neuron differentiation of human pluripotent stem cells.

Development. 2015-4-1

[10]
Glial lipid droplets and ROS induced by mitochondrial defects promote neurodegeneration.

Cell. 2015-1-15

文献AI研究员

20分钟写一篇综述,助力文献阅读效率提升50倍

立即体验

用中文搜PubMed

大模型驱动的PubMed中文搜索引擎

马上搜索

推荐工具

医学文档翻译智能文献检索