TDP‐43 Proteinopathy Presenting with Typical Symptoms of Parkinson's Disease
TDP‐43 Proteinopathy Presenting with Typical Symptoms of Parkinson's Disease
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具有帕金森病典型症状的 TDP-43 蛋白病
DOI：
10.1002/mds.29048
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发表时间：
2022
影响因子：
8.6
通讯作者：
Mochizuki Hideki
中科院分区：
文献类型：
--
作者：
Yamashita Rika;Beck Goichi;Yonenobu Yuki;Inoue Kimiko;Mitsutake Akihiko;Ishiura Hiroyuki;Hasegawa Masato;Murayama Shigeo;Mochizuki Hideki
在本研究中，我们报告了一名被诊断为临床确诊的帕金森病（PD）患者的独特发现，1神经放射学检查结果支持临床诊断;然而，尸检神经病理学检查诊断为反式反应DNA结合蛋白43 kDa（TDP-43）蛋白病，无Lewy和tau病理学。一名60岁的日本男性，没有明显的家族史，开始出现步态障碍。他被诊断为PD，因为他表现为左侧优势强直、运动迟缓和姿势不稳定。多巴胺转运蛋白单光子发射计算机断层扫描显示放射性配体摄取减少，主要发生在右侧纹状体。口服左旋多巴/脱羧酶抑制剂（150 mg/天）有效。随后，患者发生吸入性肺炎，并死于呼吸衰竭，总临床病程约为12年（临床病程详情见附录S1）。尸检时，固定前大脑重量为1076 g。观察到黑质（SN）色素脱失（图1A）。苏木精和伊红染色显示SN中严重的神经元丢失和神经胶质增生（图1B），未观察到路易体。脑干运动核团未见Bunina小体。使用针对在丝氨酸409/410残基处磷酸化的TDP-43（p-TDP-43）的第一抗体的免疫组织化学揭示了在各种脑区域中具有短营养不良神经突（DN）的神经元胞质内含物（NCI）和神经胶质胞质内含物（GCI）（图1F）。特别地，在SN中可见丰富的p-TDP-43阳性NCI/GCI/DN（图1A和1B）。图1C-E）。在红核、下橄榄核和前扣带回中可见中等量的p-TDP-43阳性NCI/GCI/DN。然而，在苍白球、壳核和丘脑底核中仅观察到少数p-TDP-43阳性NCI。同样，在中央前回中发现了一些p-TDP-43阳性GCI/DN。用抗磷酸化α-突触核蛋白（p-α-syn）和磷酸化tau（p-tau）抗体进行免疫染色，在任何脑区（包括SN、蓝斑、杏仁核和嗅球）均未发现p-α-syn和p-tau阳性NCI/GCI（神经病理学结果的详细信息见附录S1）。在佩里综合征、PD、或肌萎缩性侧索硬化症（ALS）/额颞叶变性相关基因（图1G）。重复引物聚合酶链反应显示，在9号染色体开放阅读框72（C9 orf 72）没有GGGCC重复延伸。对于免疫印迹分析，从患者的SN和前扣带回获得冷冻脑组织。结果显示对应于A型的带型（图1H）。本病例表明p-TDP-43的蓄积可独立地引起SN中的神经变性。在某些佩里综合征、2-4进行性核上性麻痹样综合征5和富含亮氨酸重复激酶2（LRRK 2）突变的家族性PD患者中，报告了SN中TDP-43相关病理学（无Lewy或tau病理学）。6我们的病人表现出典型的散发性PD临床过程。此外，反式反应DNA结合蛋白（TDP）的病理模式与TDP蛋白病，包括佩里综合征1-4和ALS伴苍白球黑质路易体变性的模式有明显区别。进一步的遗传分析显示，在动力蛋白亚基1（DCTN 1）和其他与家族性疾病相关的基因中没有突变或致病性罕见变异。
In the present study, we report unique findings in a patient who was diagnosed as clinically established Parkinson’s disease (PD), 1 and the results of neuroradiological examination supported the clinical diagnosis; however, postmortem neuropathological examination led to a diagnosis of transactive response DNA-binding protein of 43 kDa (TDP-43) proteinopathy without Lewy and tau pathology. A 60-year-old Japanese man with no apparent family history began to show gait disturbances. He was diagnosed with PD because he presented with left-predominant rigidity, bradykinesia, and postural instability. Dopamine transporter single-photon emission computed tomography revealed reduced radioligand uptake, predominantly in the right striatum. Oral administration of levodopa/decarboxylase inhibitor (150 mg/day) was effective. Subsequently, he developed aspiration pneumonia and died of respiratory failure with a total clinical course of approximately 12 years (details of the clinical course are available in Appendix S1). At autopsy, the brain weighed 1076g before fixation. Depigmentation of the substantia nigra (SN) was observed (Fig. 1A). Hematoxylin and eosin staining revealed severe neuronal loss and gliosis in the SN (Fig. 1B), and no Lewy bodies were observed. No Bunina bodies were visible in the brainstem motor nuclei. Immunohistochemistry using a primary antibody against TDP-43 phosphorylated at serine 409/410 residues (p-TDP-43) revealed neuronal cytoplasmic inclusions (NCIs) and glial cytoplasmic inclusions (GCIs) with short dystrophic neurites (DNs) in various brain areas (Fig. 1F). In particular, abundant p-TDP-43–positive NCIs/GCIs/DNs were visible in the SN (Figs. 1C–E). Moderate amounts of p-TDP-43–positive NCIs/GCIs/DNs were visible in the red nucleus, inferior olivary nucleus, and anterior cingulate gyrus. However, only a few p-TDP-43–positive NCIs were observed in the globus pallidus, putamen, and subthalamic nucleus. Similarly, a few p-TDP-43–positive GCIs/DNs were found in the precentral gyrus. Immunostaining with antiphosphorylated α-synuclein (p-α-syn) and phosphorylated tau (p-tau) antibodies did not reveal p-α-syn and p-tau–positive NCIs/GCIs in any brain area, including the SN, locus coeruleus, amygdala, and olfactory bulb (details of the neuropathological findings are available in Appendix S1).No pathogenic rare variants were found in the Perry syndrome, PD, or amyotrophic lateral sclerosis (ALS)/frontotemporal lobar degeneration–related genes analyzed by whole-exome sequencing (Fig. 1G). Repeat-primed polymerase chain reaction showed no GGGCC repeat extension in chromosome 9 open reading frame 72 (C9orf72). For immunoblot analyses, frozen brain tissue was obtained from the patient’s SN and anterior cingulate gyrus. The results showed a band pattern corresponding to type A (Fig. 1H). The present case indicates that the accumulation of p-TDP-43 could independently cause neurodegeneration in the SN. TDP-43–related pathology in the SN without Lewy or tau pathology has been reported in some patients with Perry syndrome, 2-4 progressive supranuclear palsy-like syndrome, 5 and familial PD with leucine rich repeat kinase 2 (LRRK2) mutation. 6 Our patient showed a typical clinical course of sporadic PD. Moreover, patterns of transactive response DNA-binding protein (TDP) pathology were clearly distinguishable from those of TDP proteinopathies, including Perry syndrome 1-4 and ALS with pallidonigroluysian degeneration. 7 Further genetic analyses revealed no mutations or pathogenic rare variants in dynactin subunit 1 (DCTN1) and other genes associated with familial …
影响因子：
29
作者：
Foo, Jia Nee;Chew, Elaine Guo Yan;Tan, Eng-King
通讯作者：
Tan, Eng-King