Neuronal clusterin expression is associated with cognitive protection in amyotrophic lateral sclerosis
Neuronal clusterin expression is associated with cognitive protection in amyotrophic lateral sclerosis
复制标题
DOI：
10.1111/nan.12575
复制
发表时间：
2019-08-28
影响因子：
5
通讯作者：
Smith, C.
中科院分区：
文献类型：
--
作者：
Gregory, J. M.;Elliott, E.;Smith, C.
AIMS Clusterin是一种拓扑学上动态的伴侣蛋白，能够参与细胞内和细胞外的蛋白稳定。聚集素在肌萎缩侧索硬化症(ALS)患者的脊髓中表达上调，并在动物和细胞模型中被证明对TDP-43蛋白错误折叠具有保护作用。以前的研究已经证明了TDP-43错误折叠的病理负担与ALS认知障碍之间的关系，表现出高特异性，但相应地敏感性较低，这是由于尽管TDP-43病理负担很高，但没有证据表明认知缺陷的一部分人，称为错配病例。方法假设这些病例处理蛋白质错误折叠的能力不同可能是由于保护机制的不同，如Clusterin的表达，我们评估了Clusterin和另一种伴侣蛋白HspB8在错配病例死后脑组织中的空间表达。我们使用了一种名为BaseScope的改进的原位杂交技术，具有单细胞、单转录分辨率。结果与TDP-43病理的认知表现患者相比，错配病例显示了以神经元为主的聚集素的空间表达，而TDP-43病理的认知表现则以神经胶质分布为主。结论我们的数据表明，在TDP-43病理性个体中，运动外脑区以神经元为主的Clusterin表达可能表明一种细胞保护机制，延迟了认知功能障碍等临床表现。
Aims Clusterin is a topologically dynamic chaperone protein with the ability to participate in both intra- and extacellular proteostasis. Clusterin has been shown to be upregulated in the spinal cord of patients with amyotrophic lateral sclerosis (ALS) and has been shown to protect against TDP-43 protein misfolding in animal and cell models. Previous studies have demonstrated an association between the pathological burden of TDP-43 misfolding and cognitive deficits in ALS, demonstrating high specificity, but correspondingly low sensitivity owing to a subset of individuals with no evidence of cognitive deficits despite a high burden of TDP-43 pathology, called mismatch cases. Methods Hypothesizing that differences in the ability to cope with protein misfolding in these cases may be due to differences in expression of protective mechanisms such as clusterin expression, we assessed the spatial expression of clusterin and another chaperone protein, HspB8, in post mortem brain tissue of mismatch cases. We employed a modified in situ hybridization technique called BaseScope, with single cell, single transcript resolution. Results Mismatch cases demonstrated differential spatial expression of clusterin, with a predominantly neuronal pattern, compared to cases with cognitive manifestations of their TDP-43 pathology who demonstrated a predominantly glial distribution of expression. Conclusions Our data suggest that, in individuals with TDP-43 pathology, predominantly neuronal expression of clusterin in extra-motor brain regions may indicate a cell protective mechanism delaying clinical manifestations such as cognitive dysfunction.