Dynactin is involved in Lewy body pathology
Dynactin is involved in Lewy body pathology
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DOI：
10.1111/neup.12512
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发表时间：
2018-12-01
期刊：
影响因子：
2.3
通讯作者：
Iwaki, Toru
中科院分区：
文献类型：
--
作者：
Shen, Chang;Honda, Hiroyuki;Iwaki, Toru
动力蛋白与动力蛋白形成一种蛋白质复合物，沿微管逆行运输货物。这种动力蛋白-动力蛋白复合物的功能障碍导致多种神经退行性疾病，如佩里综合征、运动神经元疾病和进行性核上性麻痹。最近，我们报道了Perry综合征中磷酸化-synuclein （p-SNCA）和dynactin最大亚基（DCTN1）在路易体（LB）样结构中的共定位。以前的报道没有集中在动力蛋白和突触核蛋白病之间的关系。因此，我们对帕金森病、痴呆伴LBs和多系统萎缩患者的尸检脑组织进行了免疫组化检测，检测了p-SNCA、DCTN1、动力蛋白2 （DCTN2、动力蛋白）和动力蛋白胞浆1中间链1 （DYNC1I1）。我们还研究了微管亲和调节激酶（MARKs），其磷酸化微管相关蛋白并触发微管破坏。脑干型和皮质型lb均为DCTN1、DCTN2、DYNC1I1和p-MARK免疫阳性，且其染色常与p-SNCA重叠。Lewy神经突也对DCTN1、DCTN2和DYNC1I1免疫阳性。然而，多系统萎缩的p- snca阳性包涵体（包括胶质和神经元细胞质包涵体）对DCTN1、DCTN2、DYNC1I1和p-MARK均呈免疫阴性。因此，dynein-dynactin复合物分子，特别是DCTN1的免疫组化可以清楚地区分LBs和神经元胞质包涵体。我们的结果表明dynactin与LB病理密切相关。
Dynactin forms a protein complex with dynein that retrogradely transports cargo along microtubules. Dysfunction of this dynein-dynactin complex causes several neurodegenerative diseases such as Perry syndrome, motor neuron diseases and progressive supranuclear palsy. Recently, we reported colocalization of phosphorylated -synuclein (p-SNCA) and the largest subunit of dynactin (DCTN1) in Lewy body (LB)-like structures in Perry syndrome. Previous reports have not focused on the relationship between dynactin and synucleinopathies. Thus, we examined autopsied human brains from patients with Parkinson's disease, dementia with LBs, and multiple system atrophy using immunohistochemistry for p-SNCA, DCTN1, dynactin 2 (DCTN2, dynamitin) and dynein cytoplasmic 1 intermediate chain 1 (DYNC1I1). We also examined microtubule affinity-regulating kinases (MARKs), which phosphorylate microtubule-associated proteins and trigger microtubule disruption. Both brainstem-type and cortical LBs were immunopositive for DCTN1, DCTN2, DYNC1I1 and p-MARK and their staining often overlapped with p-SNCA. Lewy neurites were also immunopositive for DCTN1, DCTN2 and DYNC1I1. However, p-SNCA-positive inclusions of multiple system atrophy, which included both glial and neuronal cytoplasmic inclusions, were immunonegative for DCTN1, DCTN2, DYNC1I1 and p-MARK. Thus, immunohistochemistry for dynein-dynactin complex molecules, especially DCTN1, can clearly distinguish LBs from neuronal cytoplasmic inclusions. Our results suggest that dynactin is closely associated with LB pathology.