Striatal and nigral pathology in a lentiviral rat model of Machado-Joseph disease
Striatal and nigral pathology in a lentiviral rat model of Machado-Joseph disease
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DOI：
10.1093/hmg/ddn106
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发表时间：
2008-07-15
影响因子：
3.5
通讯作者：
de Almeida, Luis Pereira
中科院分区：
文献类型：
--
作者：
Alves, Sandro;Regulier, Etienne;de Almeida, Luis Pereira
马查多-约瑟夫病(MJD)是一种致命的显性神经退行性疾病。MJD是由MJD-1基因中的多谷氨酰胺重复扩增引起的，这赋予了ataxin-3蛋白有毒的功能。在这项研究中，我们的目标是利用慢病毒载体(LV)在大鼠脑内过表达ataxin-3，以建立MJD体内遗传模型，并在定义的大脑区域研究这种疾病：黑质，MJD的影响区域，皮质和纹状体，以前没有报道的MJD影响的区域。将编码突变型或野生型人ataxin-3的LV注射到成年大鼠的脑内，检测动物的行为缺陷和神经病理异常。在转基因小鼠和人类组织中证实了纹状体病理。在黑质，突变型ataxin-3的单侧过表达导致：阿朴吗啡诱导的转身行为；泛素化ataxin-3聚集体的形成；α-突触核蛋白免疫反应；以及多巴胺能标记物(TH和VMAT2)的丢失。野生型ataxin-3过表达未见神经病理改变。突变型ataxin-3在纹状体和皮质表达，导致错误折叠的ataxin-3在纹状体内积聚，并在纹状体内丢失神经元标志物。在MJD转基因小鼠中观察到ataxin-3聚集和DARPP-32免疫反应显著降低，并通过ataxin-3包涵体在人纹状体中观察到泛素和α-突触核蛋白免疫反应，证实了纹状体的病理。本研究证明了利用LV编码突变体ataxin-3来建立MJD模型，并提供了纹状体病理的证据，表明该区域可能与一些MJD患者观察到的肌张力障碍和舞蹈症有关，并可能是治疗的靶点。
Machado-Joseph disease (MJD) is a fatal, dominant neurodegenerative disorder. MJD results from polyglutamine repeat expansion in the MJD-1 gene, conferring a toxic gain of function to the ataxin-3 protein. In this study, we aimed at overexpressing ataxin-3 in the rat brain using lentiviral vectors (LV), to generate an in vivo MJD genetic model and, to study the disorder in defined brain regions: substantia nigra, an area affected in MJD, cortex and striatum, regions not previously reported to be affected in MJD. LV encoding mutant or wild-type human ataxin-3 was injected in the brain of adult rats and the animals were tested for behavioral deficits and neuropathological abnormalities. Striatal pathology was confirmed in transgenic mice and human tissue. In substantia nigra, unilateral overexpression of mutant ataxin-3 led to: apomorphine-induced turning behavior; formation of ubiquitinated ataxin-3 aggregates; alpha-synuclein immunoreactivity; and loss of dopaminergic markers (TH and VMAT2). No neuropathological changes were observed upon wild-type ataxin-3 overexpression. Mutant ataxin-3 expression in striatum and cortex, resulted in accumulation of misfolded ataxin-3, and within striatum, loss of neuronal markers. Striatal pathology was confirmed by observation in MJD transgenic mice of ataxin-3 aggregates and substantial reduction of DARPP-32 immunoreactivity and, in human striata, by ataxin-3 inclusions, immunoreactive for ubiquitin and alpha-synuclein. This study demonstrates the use of LV encoding mutant ataxin-3 to produce a model of MJD and brings evidence of striatal pathology, suggesting that this region may contribute to dystonia and chorea observed in some MJD patients and may represent a target for therapies.