Nigrostriatal tau pathology in parkinsonism and Parkinson's disease.
Nigrostriatal tau pathology in parkinsonism and Parkinson's disease.
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DOI：
10.1093/brain/awad388
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发表时间：
2024-02-01
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影响因子：
--
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虽然帕金森病在临床上仍然由黑质纹状体变性引起的主要运动症状定义，但现在认识到该疾病通常由多种病理组成，但尚不清楚这些共同病理在疾病早期发生在何处以及它们是否是黑质纹状体变性的原因。在过去的几年里，我们一直在研究一个特征明确的运动障碍受试者队列，我们称之为轻度运动缺陷。运动缺陷是根据修改和验证的统一帕金森病评定量表III确定的，但其程度不足以诊断帕金森病。然而，在我们过去的研究中，该队列中的病例存在选择偏倚，因为需要纳入无运动缺陷和帕金森病之间的临床综合征，以及尸检定义的黑质路易病。因此，在目前的研究中，我们仅基于存在轻度运动障碍的临床表型不足以诊断帕金森病。然后，我们根据受试者是否在黑质纹状体系统中患有突触核蛋白病进一步划分该组。在这里，我们证明了黑质多巴胺能神经元的损失，壳核多巴胺能神经支配和酪氨酸羟化酶表型的损失，在黑质和壳核的损失同样发生在轻度运动缺陷组与黑质α-突触核蛋白聚集体。事实上，这两个组的共同特征是两者都具有相似程度的AT8阳性磷酸化tau，这是在年龄匹配的对照的黑质纹状体系统中未见的病理学。这些发现用早期（tau Ser208磷酸化）和晚期（tau Ser396/Ser404磷酸化）tau标志物证实。这表明黑质纹状体多巴胺能神经变性的起始独立于α-突触核蛋白聚集发生，并且可以是tau介导的。通过比较伴有和不伴有黑质突触核蛋白病的轻度运动缺陷患者和散发性帕金森病患者的大脑，Chu等人提供了证据，证明黑质纹状体多巴胺能神经变性的发生独立于α-突触核蛋白聚集，并且可以是tau介导的。有关本文的科学评论，请参见Espay和Lees（https：//doi.org/10.1093/brain/awae002）。
While Parkinson’s disease remains clinically defined by cardinal motor symptoms resulting from nigrostriatal degeneration, it is now appreciated that the disease commonly consists of multiple pathologies, but it is unclear where these co-pathologies occur early in disease and whether they are responsible for the nigrostriatal degeneration. For the past number of years, we have been studying a well-characterized cohort of subjects with motor impairment that we have termed mild motor deficits. Motor deficits were determined on a modified and validated Unified Parkinson’s Disease Rating Scale III but were insufficient in degree to diagnose Parkinson’s disease. However, in our past studies, cases in this cohort had a selection bias, as both a clinical syndrome in between no motor deficits and Parkinson’s disease, plus nigral Lewy pathology as defined post-mortem, were required for inclusion. Therefore, in the current study, we only based inclusion on the presence of a clinical phenotype with mild motor impairment insufficient to diagnose Parkinson’s disease. Then, we divided this group further based upon whether or not subjects had a synucleinopathy in the nigrostriatal system. Here we demonstrate that loss of nigral dopaminergic neurons, loss of putamenal dopaminergic innervation and loss of the tyrosine hydroxylase-phenotype in the substantia nigra and putamen occur equally in mild motor deficit groups with and without nigral alpha-synuclein aggregates. Indeed, the common feature of these two groups is that both have similar degrees of AT8 positive phosphorylated tau, a pathology not seen in the nigrostriatal system of age-matched controls. These findings were confirmed with early (tau Ser208 phosphorylation) and late (tau Ser396/Ser404 phosphorylation) tau markers. This suggests that the initiation of nigrostriatal dopaminergic neurodegeneration occurs independently of alpha-synuclein aggregation and can be tau mediated. By comparing the brains of patients with mild motor deficits with and without nigral synucleinopathy and patients with sporadic Parkinson's disease, Chu et al. provide evidence that the initiation of nigrostriatal dopaminergic neurodegeneration occurs independently of alpha-synuclein aggregation and can be tau mediated. See Espay and Lees (https://doi.org/10.1093/brain/awae002) for a scientific commentary on this article.
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影响因子：
16.2
作者：
GOEDERT, M;SPILLANTINI, MG;CROWTHER, RA
通讯作者：
CROWTHER, RA
影响因子：
12.6
作者：
Vermilyea, Scott C.;Christensen, Anne;Meints, Joyce;Singh, Balvindar;Martell-Martinez, Hector;Karim, Md. Razaul;Lee, Michael K.
通讯作者：
Lee, Michael K.
影响因子：
6.1
作者：
Chu, Yaping;Kordower, Jeffrey H.
通讯作者：
Kordower, Jeffrey H.
影响因子：
9.9
作者：
GIBB, WRG;LEES, AJ
通讯作者：
LEES, AJ
影响因子：
64.8
作者：
HARADA, A;OGUCHI, K;HIROKAWA, N
通讯作者：
HIROKAWA, N