HSPB1 mutations causing hereditary neuropathy in humans disrupt non-cell autonomous protection of motor neurons.
HSPB1 mutations causing hereditary neuropathy in humans disrupt non-cell autonomous protection of motor neurons.
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DOI：
10.1016/j.expneurol.2017.08.002
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发表时间：
2017-11
影响因子：
5.3
通讯作者：
Kolb SJ
中科院分区：
文献类型：
--
作者：
Heilman PL;Song S;Miranda CJ;Meyer K;Srivastava AK;Knapp A;Wier CG;Kaspar BK;Kolb SJ
热休克蛋白β1(HSPB1)是一种广泛表达的多功能蛋白伴侣。HSPB1基因突变导致迟发性远端遗传性运动神经病II型(DHMN)和轴索性Charcot-Marie Tooth病伴感觉受累(CMT2F)。与遗传性神经病相关的HSPB1突变的功能后果尚不清楚。HSPB1在许多神经元疾病模型中也显示出神经保护特性，包括运动神经元病肌萎缩侧索硬化症(ALS)。在疾病进展过程中，HSPB1在SOD1-ALS动物模型中上调，主要是在神经胶质细胞中。已知神经胶质细胞通过非细胞自主机制导致ALS运动神经元丢失。在这项研究中，我们研究了野生型和突变型HSPB1在ALS星形胶质细胞-运动神经元共培养模型系统中的非细胞自主作用。星形胶质细胞特异性过表达野生型HSPB1足以减轻SOD1(G93A)星形胶质细胞介导的运动神经元毒性，而过表达mutHSPB1不能减轻运动神经元的毒性。在SOD1(G93A)星形胶质细胞中表达拟磷酸化的HSPB1突变体也减少了对运动神经元的毒性，提示磷酸化可能参与了HSPB1介导的神经保护。这些数据表明，星形胶质细胞HSPB1的表达可能在运动神经元的健康和维持中发挥核心作用。
Heat shock protein beta-1 (HSPB1), is a ubiquitously expressed, multifunctional protein chaperone. Mutations in HSPB1 result in the development of a late-onset, distal hereditary motor neuropathy type II (dHMN) and axonal Charcot-Marie Tooth disease with sensory involvement (CMT2F). The functional consequences of HSPB1 mutations associated with hereditary neuropathy are unknown. HSPB1 also displays neuroprotective properties in many neuronal disease models, including the motor neuron disease amyotrophic lateral sclerosis (ALS). HSPB1 is upregulated in SOD1-ALS animal models during disease progression, predominately in glial cells. Glial cells are known to contribute to motor neuron loss in ALS through a non-cell autonomous mechanism. In this study, we examined the non-cell autonomous role of wild type and mutant HSPB1 in an astrocyte-motor neuron co-culture model system of ALS. Astrocyte-specific overexpression of wild type HSPB1 was sufficient to attenuate SOD1(G93A) astrocyte-mediated toxicity in motor neurons, whereas, overexpression of mutHSPB1 failed to ameliorate motor neuron toxicity. Expression of a phosphomimetic HSPB1 mutant in SOD1(G93A) astrocytes also reduced toxicity to motor neurons, suggesting that phosphorylation may contribute to HSPB1 mediated-neuroprotection. These data provide evidence that astrocytic HSPB1 expression may play a central role in motor neuron health and maintenance.
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DOI：
10.1074/jbc.m109.082644
发表时间：
2010-04-23
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Almeida-Souza L;Goethals S;de Winter V;Dierick I;Gallardo R;Van Durme J;Irobi J;Gettemans J;Rousseau F;Schymkowitz J;Timmerman V;Janssens S
通讯作者：
Janssens S
影响因子：
4.1
作者：
Bryantsev, Anton L.;Kurchashova, Svetlana Yu.;Kampinga, Harm H.
通讯作者：
Kampinga, Harm H.
影响因子：
82.9
作者：
d'Ydewalle, Constantin;Krishnan, Jyothsna;Van Den Bosch, Ludo
通讯作者：
Van Den Bosch, Ludo
影响因子：
46.9
作者：
通讯作者：
--
影响因子：
12.4
作者：
Dodge, James C.;Haidet, Amanda M.;Kaspar, Brian K.
通讯作者：
Kaspar, Brian K.