成年小鼠体内 ATP13A2 的缺失会诱发进行性黑质通路多巴胺能退化和溶酶体异常。

IF 6.7 1区 医学 Q1 NEUROSCIENCES NPJ Parkinson's Disease Pub Date : 2024-07-20 DOI:10.1038/s41531-024-00748-5
Madalynn L Erb, Kayla Sipple, Nathan Levine, Xi Chen, Darren J Moore
{"title":"成年小鼠体内 ATP13A2 的缺失会诱发进行性黑质通路多巴胺能退化和溶酶体异常。","authors":"Madalynn L Erb, Kayla Sipple, Nathan Levine, Xi Chen, Darren J Moore","doi":"10.1038/s41531-024-00748-5","DOIUrl":null,"url":null,"abstract":"<p><p>Although most cases of Parkinson's disease (PD) are sporadic, mutations in over 20 genes are known to cause heritable forms of the disease. Recessive loss-of-function mutations in ATP13A2, a lysosomal transmembrane P5<sub>B</sub>-type ATPase and polyamine exporter, can cause early-onset familial PD. Familial ATP13A2 mutations are also linked to related neurodegenerative diseases, including Kufor-Rakeb syndrome, hereditary spastic paraplegias, neuronal ceroid lipofuscinosis, and amyotrophic lateral sclerosis. Despite the severe effects of ATP13A2 mutations in humans, ATP13A2 knockout (KO) mice fail to exhibit neurodegeneration even at advanced ages, making it challenging to study the neuropathological effects of ATP13A2 loss in vivo. Germline deletion of ATP13A2 in rodents may trigger the upregulation of compensatory pathways during embryonic development that mask the full neurotoxic effects of ATP13A2 loss in the brain. To explore this idea, we selectively deleted ATP13A2 in the adult mouse brain by the unilateral delivery of an AAV-Cre vector into the substantia nigra of young adult mice carrying conditional loxP-flanked ATP13A2 KO alleles. We observe a progressive loss of striatal dopaminergic nerve terminals at 3 and 10 months after AAV-Cre delivery. Cre-injected mice also exhibit robust dopaminergic neuronal degeneration in the substantia nigra at 10 months. Adult-onset ATP13A2 KO also recreates many of the phenotypes observed in aged germline ATP13A2 KO mice, including lysosomal abnormalities, p62-positive inclusions, and neuroinflammation. Our study demonstrates that the adult-onset homozygous deletion of ATP13A2 in the nigrostriatal pathway produces robust and progressive dopaminergic neurodegeneration that serves as a useful in vivo model of ATP13A2-related neurodegenerative diseases.</p>","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":null,"pages":null},"PeriodicalIF":6.7000,"publicationDate":"2024-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11271504/pdf/","citationCount":"0","resultStr":"{\"title\":\"Adult-onset deletion of ATP13A2 in mice induces progressive nigrostriatal pathway dopaminergic degeneration and lysosomal abnormalities.\",\"authors\":\"Madalynn L Erb, Kayla Sipple, Nathan Levine, Xi Chen, Darren J Moore\",\"doi\":\"10.1038/s41531-024-00748-5\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Although most cases of Parkinson's disease (PD) are sporadic, mutations in over 20 genes are known to cause heritable forms of the disease. Recessive loss-of-function mutations in ATP13A2, a lysosomal transmembrane P5<sub>B</sub>-type ATPase and polyamine exporter, can cause early-onset familial PD. Familial ATP13A2 mutations are also linked to related neurodegenerative diseases, including Kufor-Rakeb syndrome, hereditary spastic paraplegias, neuronal ceroid lipofuscinosis, and amyotrophic lateral sclerosis. Despite the severe effects of ATP13A2 mutations in humans, ATP13A2 knockout (KO) mice fail to exhibit neurodegeneration even at advanced ages, making it challenging to study the neuropathological effects of ATP13A2 loss in vivo. Germline deletion of ATP13A2 in rodents may trigger the upregulation of compensatory pathways during embryonic development that mask the full neurotoxic effects of ATP13A2 loss in the brain. To explore this idea, we selectively deleted ATP13A2 in the adult mouse brain by the unilateral delivery of an AAV-Cre vector into the substantia nigra of young adult mice carrying conditional loxP-flanked ATP13A2 KO alleles. We observe a progressive loss of striatal dopaminergic nerve terminals at 3 and 10 months after AAV-Cre delivery. Cre-injected mice also exhibit robust dopaminergic neuronal degeneration in the substantia nigra at 10 months. Adult-onset ATP13A2 KO also recreates many of the phenotypes observed in aged germline ATP13A2 KO mice, including lysosomal abnormalities, p62-positive inclusions, and neuroinflammation. Our study demonstrates that the adult-onset homozygous deletion of ATP13A2 in the nigrostriatal pathway produces robust and progressive dopaminergic neurodegeneration that serves as a useful in vivo model of ATP13A2-related neurodegenerative diseases.</p>\",\"PeriodicalId\":19706,\"journal\":{\"name\":\"NPJ Parkinson's Disease\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":6.7000,\"publicationDate\":\"2024-07-20\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11271504/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"NPJ Parkinson's Disease\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1038/s41531-024-00748-5\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"NEUROSCIENCES\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"NPJ Parkinson's Disease","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1038/s41531-024-00748-5","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"NEUROSCIENCES","Score":null,"Total":0}
引用次数: 0

摘要

尽管大多数帕金森病(PD)病例都是散发性的,但已知有 20 多个基因的突变可导致该病的遗传形式。ATP13A2 是一种溶酶体跨膜 P5B 型 ATP 酶和多胺输出体,其隐性功能缺失突变可导致早发性家族性帕金森病。家族性 ATP13A2 基因突变还与相关的神经退行性疾病有关,包括 Kufor-Rakeb 综合征、遗传性痉挛性截瘫、神经细胞类脂质硬化症和肌萎缩侧索硬化症。尽管 ATP13A2 基因突变对人类有严重影响,但 ATP13A2 基因敲除(KO)小鼠即使在高龄时也不会出现神经变性,因此研究 ATP13A2 基因缺失对体内神经病理学的影响具有挑战性。啮齿类动物体内 ATP13A2 的种系缺失可能会在胚胎发育过程中引发代偿途径的上调,从而掩盖 ATP13A2 缺失在大脑中的全部神经毒性效应。为了探讨这一观点,我们通过向携带条件性loxP-flanked ATP13A2 KO等位基因的年轻成年小鼠的黑质单侧递送AAV-Cre载体,选择性地在成年小鼠大脑中删除了ATP13A2。我们观察到,在 AAV-Cre 植入 3 个月和 10 个月后,纹状体多巴胺能神经末梢逐渐丧失。在 10 个月时,Cre 注入的小鼠黑质中的多巴胺能神经元也出现了严重的变性。成年型 ATP13A2 KO 也重现了在老年型种系 ATP13A2 KO 小鼠中观察到的许多表型,包括溶酶体异常、p62 阳性包涵体和神经炎症。我们的研究表明,黑质通路中的 ATP13A2 在成年后发生同基因缺失,会产生强有力的进行性多巴胺能神经退行性变,可作为 ATP13A2 相关神经退行性疾病的有用体内模型。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

摘要图片

查看原文
分享 分享
微信好友 朋友圈 QQ好友 复制链接
本刊更多论文
Adult-onset deletion of ATP13A2 in mice induces progressive nigrostriatal pathway dopaminergic degeneration and lysosomal abnormalities.

Although most cases of Parkinson's disease (PD) are sporadic, mutations in over 20 genes are known to cause heritable forms of the disease. Recessive loss-of-function mutations in ATP13A2, a lysosomal transmembrane P5B-type ATPase and polyamine exporter, can cause early-onset familial PD. Familial ATP13A2 mutations are also linked to related neurodegenerative diseases, including Kufor-Rakeb syndrome, hereditary spastic paraplegias, neuronal ceroid lipofuscinosis, and amyotrophic lateral sclerosis. Despite the severe effects of ATP13A2 mutations in humans, ATP13A2 knockout (KO) mice fail to exhibit neurodegeneration even at advanced ages, making it challenging to study the neuropathological effects of ATP13A2 loss in vivo. Germline deletion of ATP13A2 in rodents may trigger the upregulation of compensatory pathways during embryonic development that mask the full neurotoxic effects of ATP13A2 loss in the brain. To explore this idea, we selectively deleted ATP13A2 in the adult mouse brain by the unilateral delivery of an AAV-Cre vector into the substantia nigra of young adult mice carrying conditional loxP-flanked ATP13A2 KO alleles. We observe a progressive loss of striatal dopaminergic nerve terminals at 3 and 10 months after AAV-Cre delivery. Cre-injected mice also exhibit robust dopaminergic neuronal degeneration in the substantia nigra at 10 months. Adult-onset ATP13A2 KO also recreates many of the phenotypes observed in aged germline ATP13A2 KO mice, including lysosomal abnormalities, p62-positive inclusions, and neuroinflammation. Our study demonstrates that the adult-onset homozygous deletion of ATP13A2 in the nigrostriatal pathway produces robust and progressive dopaminergic neurodegeneration that serves as a useful in vivo model of ATP13A2-related neurodegenerative diseases.

求助全文
通过发布文献求助,成功后即可免费获取论文全文。 去求助
来源期刊
NPJ Parkinson's Disease
NPJ Parkinson's Disease Medicine-Neurology (clinical)
CiteScore
9.80
自引率
5.70%
发文量
156
审稿时长
11 weeks
期刊介绍: npj Parkinson's Disease is a comprehensive open access journal that covers a wide range of research areas related to Parkinson's disease. It publishes original studies in basic science, translational research, and clinical investigations. The journal is dedicated to advancing our understanding of Parkinson's disease by exploring various aspects such as anatomy, etiology, genetics, cellular and molecular physiology, neurophysiology, epidemiology, and therapeutic development. By providing free and immediate access to the scientific and Parkinson's disease community, npj Parkinson's Disease promotes collaboration and knowledge sharing among researchers and healthcare professionals.
期刊最新文献
Transcranial direct current stimulation for Parkinson’s disease: systematic review and meta-analysis of motor and cognitive effects The p.Gly2019Ser is a common LRRK2 pathogenic variant among Egyptians with familial and sporadic Parkinson's disease. Systemic inflammation accelerates neurodegeneration in a rat model of Parkinson's disease overexpressing human alpha synuclein. The effect of pallidal stimulation on sleep outcomes and related brain connectometries in Parkinson’s disease Subthalamic stimulation causally modulates human voluntary decision-making to stay or go.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
已复制链接
已复制链接
快去分享给好友吧!
我知道了
×
扫码分享
扫码分享
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1