Tiloca Cinzia, Goldwurm Stefano, Calcagno Narghes, Verde Federico, Peverelli Silvia, Calini Daniela, Zecchinelli Anna Lena, Sangalli Davide, Ratti Antonia, Pezzoli Gianni, Silani Vincenzo, Ticozzi Nicola
Department of Neurology and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano, Milan, Italy.
Parkinson Institute of Milan, ASST Gaetano Pini/CTO, Milan, Italy.
Front Aging Neurosci. 2022 Sep 29;14:1020948. doi: 10.3389/fnagi.2022.1020948. eCollection 2022.
Aggregates of TAR DNA-binding protein of 43 kDa (TDP-43) represent the pathological hallmark of most amyotrophic lateral sclerosis (ALS) and of nearly 50% of frontotemporal dementia (FTD) cases but were also observed to occur as secondary neuropathology in the nervous tissue of patients with different neurodegenerative diseases, including Parkinson's disease (PD) and atypical parkinsonism. Mutations of gene, mainly in exon 6 hotspot, have been reported to be causative of some forms of ALS and FTD, with clinical signs of parkinsonism observed in few mutation carriers.
Direct DNA sequencing of exon 6 was performed in a large Italian cohort of 735 patients affected by PD (354 familial and 381 sporadic) and 142 affected by atypical parkinsonism, including 39 corticobasal syndrome (CBS) and 103 progressive sopranuclear palsy (PSP). Sequencing data from 1710 healthy, ethnically matched controls were already available.
Four missense variants (p.N267S, p. G294A, p.G295S, p.S393L) were identified in four patients with typical PD and in two individuals with atypical parkinsonism (1 CBS and 1 PSP). None of the detected mutations were found in healthy controls and only the variant p.N267S was previously described in association to idiopathic familial and sporadic PD and to CBS.
In this study we provide further insight into the clinical phenotypic heterogeneity associated with mutations, which expands beyond the classical ALS and FTD diseases to include also PD and atypical parkinsonism, although with a low mutational frequency, varying considerably in different Caucasian populations. In addition, our study extends the spectrum of pathogenetic mutations found in familial and sporadic PD.
43 kDa的TAR DNA结合蛋白（TDP-43）聚集体是大多数肌萎缩侧索硬化症（ALS）和近50%的额颞叶痴呆（FTD）病例的病理标志，但在包括帕金森病（PD）和非典型帕金森综合征在内的不同神经退行性疾病患者的神经组织中也被观察到作为继发性神经病理学出现。据报道，该基因的突变主要在外显子6热点区域，是某些形式的ALS和FTD的病因，少数突变携带者有帕金森综合征的临床症状。
对意大利一个大型队列中的735例PD患者（354例家族性和381例散发性）和142例非典型帕金森综合征患者进行外显子6的直接DNA测序，其中非典型帕金森综合征患者包括39例皮质基底节综合征（CBS）和103例进行性核上性麻痹（PSP）。已有1710名种族匹配的健康对照的测序数据。
在4例典型PD患者和2例非典型帕金森综合征患者（1例CBS和1例PSP）中鉴定出4个错义变体（p.N267S、p.G294A、p.G295S、p.S393L）。在健康对照中未发现检测到的突变，只有变体p.N267S先前有与特发性家族性和散发性PD以及CBS相关的报道。
在本研究中，我们进一步深入了解了与该基因突变相关的临床表型异质性，其范围超出了经典的ALS和FTD疾病，还包括PD和非典型帕金森综合征，尽管突变频率较低，在不同白种人群中差异很大。此外，我们的研究扩展了在家族性和散发性PD中发现的该基因致病突变的范围。
