X-linked SBMA model mice display relevant non-neurological phenotypes and their expression of mutant androgen receptor protein in motor neurons is not required for neuromuscular disease.
X-linked SBMA model mice display relevant non-neurological phenotypes and their expression of mutant androgen receptor protein in motor neurons is not required for neuromuscular disease.
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DOI：
10.1186/s40478-023-01582-1
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发表时间：
2023-06-02
影响因子：
7.1
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中科院分区：
文献类型：
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X连锁脊髓和延髓肌萎缩症（SBMA；肯尼迪病）是一种罕见的神经肌肉疾病，其特征是成人发病的近端肌肉无力和下运动神经元变性。 SBMA 是第一种被发现由重复扩展突变引起的人类疾病，因为受影响的患者在雄激素受体 (AR) 基因中拥有编码多聚谷氨酰胺的扩展的 CAG 重复序列。我们之前开发了 SBMA 的条件 BAC fxAR121 转基因小鼠模型，并用它来定义多聚谷氨酰胺扩增 AR 的骨骼肌表达在引起运动神经元变性中的主要作用。在这里，我们试图通过对 BAC fxAR121 小鼠进行详细检查和定向实验来扩展我们对 SBMA 疾病病理生理学和细胞基础的理解。首先，我们评估了 BAC fxAR121 小鼠最近在人类 SBMA 患者中描述的非神经疾病表型，并记录了老年雄性 BAC fxAR121 小鼠中显着的非酒精性脂肪肝病、心脏肥大和心室心壁变薄。我们在 SBMA 小鼠中发现显着的肝脏和心脏异常，这强调了评估人类 SBMA 患者的肝脏和心脏病体征的必要性。为了直接检查运动神经元表达的 PolyQ-AR 蛋白对 SBMA 神经变性的贡献，我们将 BAC fxAR121 小鼠与运动神经元中表达 Cre 重组酶的两种不同品系的转基因小鼠杂交，在更新我们当前 BAC fxAR121 菌落中 SBMA 表型的特征后，我们发现从运动神经元中切除突变 AR 并不能挽救神经肌肉或全身性疾病。这些发现进一步证实了骨骼肌作为 SBMA 运动神经元病驱动因素的主要作用，并表明正在开发的治疗患者的疗法应外周给药。在线版本包含可在 10.1186/s40478-023-01582-1 获取的补充材料。
X-linked spinal and bulbar muscular atrophy (SBMA; Kennedy's disease) is a rare neuromuscular disorder characterized by adult-onset proximal muscle weakness and lower motor neuron degeneration. SBMA was the first human disease found to be caused by a repeat expansion mutation, as affected patients possess an expanded tract of CAG repeats, encoding polyglutamine, in the androgen receptor (AR) gene. We previously developed a conditional BAC fxAR121 transgenic mouse model of SBMA and used it to define a primary role for skeletal muscle expression of polyglutamine-expanded AR in causing the motor neuron degeneration. Here we sought to extend our understanding of SBMA disease pathophysiology and cellular basis by detailed examination and directed experimentation with the BAC fxAR121 mice. First, we evaluated BAC fxAR121 mice for non-neurological disease phenotypes recently described in human SBMA patients, and documented prominent non-alcoholic fatty liver disease, cardiomegaly, and ventricular heart wall thinning in aged male BAC fxAR121 mice. Our discovery of significant hepatic and cardiac abnormalities in SBMA mice underscores the need to evaluate human SBMA patients for signs of liver and heart disease. To directly examine the contribution of motor neuron-expressed polyQ-AR protein to SBMA neurodegeneration, we crossed BAC fxAR121 mice with two different lines of transgenic mice expressing Cre recombinase in motor neurons, and after updating characterization of SBMA phenotypes in our current BAC fxAR121 colony, we found that excision of mutant AR from motor neurons did not rescue neuromuscular or systemic disease. These findings further validate a primary role for skeletal muscle as the driver of SBMA motor neuronopathy and indicate that therapies being developed to treat patients should be delivered peripherally. The online version contains supplementary material available at 10.1186/s40478-023-01582-1.
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影响因子：
12.7
作者：
Ditsworth D;Maldonado M;McAlonis-Downes M;Sun S;Seelman A;Drenner K;Arnold E;Ling SC;Pizzo D;Ravits J;Cleveland DW;Da Cruz S
通讯作者：
Da Cruz S
影响因子：
5.7
作者：
Bunting, Emma L.;Hamilton, Joseph;Tabrizi, Sarah J.
通讯作者：
Tabrizi, Sarah J.
影响因子：
48
作者：
Grunseich, Christopher;Miller, Ram;Fischbeck, Kenneth H.
通讯作者：
Fischbeck, Kenneth H.
影响因子：
2.8
作者：
Grunseich, Christopher;Kats, Ilona R.;Bott, Laura C.;Rinaldi, Carlo;Kokkinis, Angela;Fox, Derrick;Chen, Ke-lian;Schindler, Alice B.;Mankodi, Ami K.;Shrader, Joseph A.;Schwartz, Daniel P.;Lehky, Tanya J.;Liu, Chia-Ying;Fischbeck, Kenneth H.
通讯作者：
Fischbeck, Kenneth H.
影响因子：
64.8
作者：
LASPADA, AR;WILSON, EM;FISCHBECK, KH
通讯作者：
FISCHBECK, KH