The hereditary spastic paraplegia protein strumpellin: characterisation in neurons and of the effect of disease mutations on WASH complex assembly and function.
The hereditary spastic paraplegia protein strumpellin: characterisation in neurons and of the effect of disease mutations on WASH complex assembly and function.
复制标题
DOI：
10.1016/j.bbadis.2012.10.011
复制
发表时间：
2013-01
影响因子：
6.2
通讯作者：
Reid, Evan
中科院分区：
文献类型：
--
作者：
Freeman, Caroline;Seaman, Matthew N. J.;Reid, Evan
编码strumpellin的基因突变导致常染色体显性遗传性痉挛性截瘫（HSP），其中存在皮质脊髓束轴突变性。Strumpellin是WASH复合体的一个组成部分，WASH复合体是一种肌动蛋白调节复合体，通过与反转录复合体的相互作用被招募到核内体中。神经元中WASH复合物及其与逆转录物的关系尚未完全表征，strumpellin突变的分子病理机制尚不清楚。在这里，我们证明了WASH复合物在大脑中组装，在那里它与反转录物相互作用。这两种复合物的成员在初级皮质神经元中彼此共定位并与核内体共定位，并且存在于躯体-树突和轴突室中。我们发现strumpellin不是正常转铁蛋白受体运输所必需的，但却是β-2-肾上腺素能受体的正确亚细胞分布所必需的。然而，strumpellin病突变不影响其与WASH复合体的结合或其亚细胞定位，也不影响WASH复合体的功能，包括调节内体管化、转铁蛋白受体运输或β-2-肾上腺素能受体定位。WASH复合体的模型表明它含有单个strumpellin分子，因此在strumpellin突变的患者中，含有野生型和突变型strumpellin的复合体应该以相同的数量存在。在大多数细胞类型中，这将提供足够的功能性WASH以允许正常的细胞生理。然而，由于其异常长的轴突对膜交通的要求，我们认为皮质脊髓神经元特别容易受到功能性WASH减少的影响。我们研究了痉挛性截瘫蛋白strumpellin，它是WASH复合体的一个组成部分。WASH复合物在神经元中与内体上的反转录物相互作用。WASH和retromer位于轴突，这是遗传性痉挛性截瘫病理的部位。Strumpellin调节β-2-肾上腺素能受体的亚细胞分布。疾病突变体对strumpellin的细胞功能没有显性影响。
Mutations in the gene encoding strumpellin cause autosomal dominant hereditary spastic paraplegia (HSP), in which there is degeneration of corticospinal tract axons. Strumpellin is a component of the WASH complex, an actin-regulating complex that is recruited to endosomes by interactions with the retromer complex. The WASH complex and its relationship to retromer have not been fully characterised in neurons, and the molecular pathological mechanism of strumpellin mutation is unclear. Here we demonstrate that the WASH complex assembles in the brain, where it interacts with retromer. Members of both complexes co-localise with each other and with endosomes in primary cortical neurons, and are present in somato-dendritic and axonal compartments. We show that strumpellin is not required for normal transferrin receptor traffic, but is required for the correct subcellular distribution of the β-2-adrenergic receptor. However, strumpellin disease mutations do not affect its incorporation into the WASH complex or its subcellular localisation, nor do they have a dominant effect on functions of the WASH complex, including regulation of endosomal tubulation, transferrin receptor traffic or β-2-adrenergic receptor localisation. Models of the WASH complex indicate that it contains a single strumpellin molecule, so in patients with strumpellin mutations, complexes containing wild-type and mutant strumpellin should be present in equal numbers. In most cell types this would provide sufficient functional WASH to allow normal cellular physiology. However, owing to the demands on membrane traffic imposed by their exceptionally long axons, we suggest that corticospinal neurons are especially vulnerable to reductions in functional WASH. ► We studied the spastic paraplegia protein strumpellin, a component of WASH complex. ► The WASH complex assembles in neurons where it interacts with retromer on endosomes. ► WASH and retromer are in axons, the site of hereditary spastic paraplegia pathology. ► Strumpellin regulates the subcellular distribution of the β-2-adrenergic receptor. ► Disease mutants do not have a dominant effect on cellular functions of strumpellin.
登录
查看更多内容
影响因子：
4
作者：
Seaman, Matthew N. J.;Harbour, Michael E.;Bright, Nicholas
通讯作者：
Bright, Nicholas
DOI：
10.1083/jcb.201009052
发表时间：
2011-04-04
期刊：
The Journal of cell biology
影响因子：
--
作者：
Rodal AA;Blunk AD;Akbergenova Y;Jorquera RA;Buhl LK;Littleton JT
通讯作者：
Littleton JT
影响因子：
5.3
作者：
Fischer, LR;Culver, DG;Glass, JD
通讯作者：
Glass, JD
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：
10.1038/nrn2946
发表时间：
2011-01
期刊：
Nature reviews. Neuroscience
影响因子：
--
作者：
Blackstone C;O'Kane CJ;Reid E
通讯作者：
Reid E