Neuronal VPS35 deletion induces spinal cord motor neuron degeneration and early post-natal lethality.
Neuronal VPS35 deletion induces spinal cord motor neuron degeneration and early post-natal lethality.
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DOI：
10.1093/braincomms/fcab208
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发表时间：
2021
影响因子：
4.8
通讯作者：
Moore DJ
中科院分区：
文献类型：
--
作者：
Sargent D;Cunningham LA;Dues DJ;Ma Y;Kordich JJ;Mercado G;Brundin P;Cowell RM;Moore DJ
神经退行性疾病的特征是不同脑区神经元群的选择性变性，并且经常形成不同的蛋白质聚集体，这些聚集体经常在疾病之间重叠。虽然许多散发性神经退行性疾病的病因尚不清楚，但与家族性或散发性疾病相关的基因以及所涉及的潜在细胞途径倾向于支持常见的疾病机制。强调这一概念的是，空泡蛋白分类35同源基因（VPS35）突变已被确定为迟发性常染色体显性家族性帕金森病的病因，而在阿尔茨海默病、进行性核上性麻痹和匹克病等神经退行性tau病和肌萎缩性侧索硬化症患者的易感脑区，VPS35蛋白水平降低。因此，VPS35通常与许多神经退行性疾病有关。VPS35在反转录复合体中起关键作用，该复合体介导从核内体到反式高尔基网络或质膜的跨膜蛋白货物的检索和再循环。VPS35及其反转录功能在真核细胞中高度保守，VPS35的纯合缺失在小鼠中诱导早期胚胎致死，阻碍了对其在大脑中的作用的理解。在这里，我们培养了选择性缺失神经元中VPS35的条件敲除小鼠，以更好地阐明其在神经元活力中的作用及其与神经退行性疾病的联系。令人惊讶的是，VPS35的泛神经元缺失诱导了一种进行性和快速的疾病，伴有运动缺陷和早期产后死亡。这种神经表型的基础是脊髓运动神经元的相对选择性和健壮性变性。神经元丢失伴随着p62阳性蛋白包涵体的形成和强烈的反应性星形胶质细胞形成。我们的研究揭示了VPS35功能在出生后发育过程中运动神经元的正常维持和存活中一个关键但未被认识到的作用，这对神经退行性疾病，特别是肌萎缩侧索硬化症具有重要意义。Sargent和Cunningham等人报道了VPS35泛神经元缺失的条件敲除小鼠。VPS35条件敲除小鼠表现出运动缺陷和早期产后死亡，这是由脊髓运动神经元的选择性变性引起的，并伴有明显的反应性胶质瘤。他们的发现可能对肌萎缩性侧索硬化症有重要意义。
Neurodegenerative diseases are characterized by the selective degeneration of neuronal populations in different brain regions and frequently the formation of distinct protein aggregates that often overlap between diseases. While the causes of many sporadic neurodegenerative diseases are unclear, genes associated with familial or sporadic forms of disease and the underlying cellular pathways involved tend to support common disease mechanisms. Underscoring this concept, mutations in the Vacuolar Protein Sorting 35 Orthologue (VPS35) gene have been identified to cause late-onset, autosomal dominant familial Parkinson’s disease, whereas reduced VPS35 protein levels are reported in vulnerable brain regions of subjects with Alzheimer’s disease, neurodegenerative tauopathies such as progressive supranuclear palsy and Pick’s disease, and amyotrophic lateral sclerosis. Therefore, VPS35 is commonly implicated in many neurodegenerative diseases. VPS35 plays a critical role in the retromer complex that mediates the retrieval and recycling of transmembrane protein cargo from endosomes to the trans-Golgi network or plasma membrane. VPS35 and retromer function are highly conserved in eukaryotic cells, with the homozygous deletion of VPS35 inducing early embryonic lethality in mice that has hindered an understanding of its role in the brain. Here, we develop conditional knockout mice with the selective deletion of VPS35 in neurons to better elucidate its role in neuronal viability and its connection to neurodegenerative diseases. Surprisingly, the pan-neuronal deletion of VPS35 induces a progressive and rapid disease with motor deficits and early post-natal lethality. Underlying this neurological phenotype is the relatively selective and robust degeneration of motor neurons in the spinal cord. Neuronal loss is accompanied and preceded by the formation of p62-positive protein inclusions and robust reactive astrogliosis. Our study reveals a critical yet unappreciated role for VPS35 function in the normal maintenance and survival of motor neurons during post-natal development that has important implications for neurodegenerative diseases, particularly amyotrophic lateral sclerosis. Sargent and Cunningham et al. report conditional knockout mice with pan-neuronal deletion of VPS35. The VPS35 conditional knockout mice exhibit motor deficits and early post-natal lethality that resulted from the selective degeneration of spinal cord motor neurons accompanied by marked reactive gliosis. Their findings may have important implications for amyotrophic lateral sclerosis.
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DOI：
10.1038/s41531-018-0063-3
发表时间：
2018
期刊：
NPJ Parkinson's disease
影响因子：
--
作者：
Cataldi S;Follett J;Fox JD;Tatarnikov I;Kadgien C;Gustavsson EK;Khinda J;Milnerwood AJ;Farrer MJ
通讯作者：
Farrer MJ
影响因子：
6.1
作者：
Guerreiro R;Gibbons E;Tábuas-Pereira M;Kun-Rodrigues C;Santo GC;Bras J
通讯作者：
Bras J
影响因子：
64.5
作者：
Saunders A;Macosko EZ;Wysoker A;Goldman M;Krienen FM;de Rivera H;Bien E;Baum M;Bortolin L;Wang S;Goeva A;Nemesh J;Kamitaki N;Brumbaugh S;Kulp D;McCarroll SA
通讯作者：
McCarroll SA
DOI：
10.1083/jcb.137.1.79
发表时间：
1997-04-07
期刊：
The Journal of cell biology
影响因子：
--
作者：
Seaman MN;Marcusson EG;Cereghino JL;Emr SD
通讯作者：
Emr SD
DOI：
10.1042/bcj20180248
发表时间：
2018-06-06
期刊：
The Biochemical journal
影响因子：
--
作者：
Mir R;Tonelli F;Lis P;Macartney T;Polinski NK;Martinez TN;Chou MY;Howden AJM;König T;Hotzy C;Milenkovic I;Brücke T;Zimprich A;Sammler E;Alessi DR
通讯作者：
Alessi DR