Shen Chang, Honda Hiroyuki, Suzuki Satoshi O, Maeda Norihisa, Shijo Masahiro, Hamasaki Hideomi, Sasagasako Naokazu, Fujii Naoki, Iwaki Toru
Department of Neuropathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Department of Neurology, Neuro-Muscular Center, National Omuta Hospital, Fukuoka, Japan.
Neuropathology. 2018 Dec;38(6):583-590. doi: 10.1111/neup.12512. Epub 2018 Sep 14.
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 α-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.
动力蛋白激活蛋白与动力蛋白形成一种蛋白质复合物，该复合物沿微管逆行运输货物。这种动力蛋白 - 动力蛋白激活蛋白复合物功能障碍会引发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，我们报道了在佩里综合征患者的路易小体（LB）样结构中磷酸化α-突触核蛋白（p-SNCA）与动力蛋白激活蛋白的最大亚基（DCTN1）共定位。以往的报道尚未关注动力蛋白激活蛋白与突触核蛋白病之间的关系。因此，我们使用针对p-SNCA、DCTN1、动力蛋白激活蛋白2（DCTN2，动力蛋白抑制素）和动力蛋白胞质1中间链1（DYNC1I1）的免疫组织化学方法，对帕金森病、路易小体痴呆和多系统萎缩患者的尸检人脑进行了检查。我们还检测了微管亲和力调节激酶（MARKs），其可磷酸化微管相关蛋白并引发微管破坏。脑干型和皮质型路易小体对DCTN1、DCTN2、DYNC1I1和p-MARK均呈免疫阳性，且它们的染色常与p-SNCA重叠。路易神经突对DCTN1、DCTN2和DYNC1I1也呈免疫阳性。然而，多系统萎缩的p-SNCA阳性包涵体，包括神经胶质和神经元胞质包涵体，对DCTN1、DCTN2、DYNC1I1和p-MARK均呈免疫阴性。因此，针对动力蛋白 - 动力蛋白激活蛋白复合物分子，尤其是DCTN1的免疫组织化学方法，可清晰地区分路易小体与神经元胞质包涵体。我们的结果表明，动力蛋白激活蛋白与路易小体病理密切相关。
