Department of Neuroscience, Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield S10 2HQ, UK.
Acta Neuropathol. 2011 Dec;122(6):657-71. doi: 10.1007/s00401-011-0913-0. Epub 2011 Nov 22.
Research into amyotrophic lateral sclerosis (ALS) has been stimulated by a series of genetic and molecular pathology discoveries. The hallmark neuronal cytoplasmic inclusions of sporadic ALS (sALS) predominantly comprise a nuclear RNA processing protein, TDP-43 encoded by the gene TARDBP, a discovery that emerged from high throughput analysis of human brain tissue from patients with frontotemporal dementia (FTD) who share a common molecular pathology with ALS. The link between RNA processing and ALS was further strengthened by the discovery that another genetic locus linking familial ALS (fALS) and FTD was due to mutation of the fused in sarcoma (FUS) gene. Of potentially even greater importance it emerges that TDP-43 accumulation and inclusion formation characterises not only most sALS cases but also those that arise from mutations in several genes including TARDBP (predominantly ALS cases) itself, C9ORF72 (ALS and FTD cases), progranulin (predominantly FTD phenotypes), VAPB (predominantly ALS cases) and in some ALS cases with rare genetic variants of uncertain pathogenicity (CHMP2B). "TDP-proteinopathy" therefore now represents a final common pathology associated with changes in multiple genes and opens the possibility of research by triangulation towards key common upstream molecular events. It also delivers final proof of the hypothesis that ALS and most FTD cases are disorders within a common pathology expressed as a clinico-anatomical spectrum. The emergence of TDP-proteinopathy also confirms the view that glial pathology is a crucial facet in this class of neurodegeneration, adding to the established view of non-nerve cell autonomous degeneration of the motor system from previous research on SOD1 fALS. Future research into the mechanisms of TDP-43 and FUS-related neurodegeneration, taking into account the major component of glial pathology now revealed in those disorders will significantly accelerate new discoveries in this field, including target identification for new therapy.
对肌萎缩侧索硬化症（ALS）的研究受到一系列遗传和分子病理学发现的刺激。散发性 ALS（sALS）的标志性神经元细胞质包含物主要由 TDP-43 组成，该蛋白由 TARDBP 基因编码，该发现源自对具有与 ALS 共同分子病理学的额颞叶痴呆（FTD）患者的人脑组织进行高通量分析。RNA 处理与 ALS 之间的联系进一步得到加强，因为发现另一个将家族性 ALS（fALS）和 FTD 联系起来的遗传基因座是由于肉瘤融合（FUS）基因的突变。具有更大潜在重要性的是，TDP-43 的积累和包含物形成不仅是大多数 sALS 病例的特征，而且还与包括 TARDBP（主要是 ALS 病例）本身、C9ORF72（ALS 和 FTD 病例）、颗粒蛋白（主要是 FTD 表型）、VAPB（主要是 ALS 病例）在内的几个基因的突变有关，并且在一些具有不确定致病性的罕见遗传变异的 ALS 病例中也是如此（CHMP2B）。因此，“TDP-蛋白病”现在代表与多个基因变化相关的最终共同病理学，并为通过三角测量法研究关键的共同上游分子事件提供了可能性。它还提供了最终证据证明 ALS 和大多数 FTD 病例是一种共同病理学下的疾病，表现为临床解剖谱。TDP-蛋白病的出现也证实了这样一种观点，即神经胶质病理学是神经退行性变这一类疾病的一个关键方面，这增加了从以前关于 SOD1 fALS 的研究中对非神经细胞自主运动系统变性的已有观点。考虑到在这些疾病中现在揭示的神经胶质病理学的主要组成部分，对 TDP-43 和 FUS 相关神经退行性变机制的进一步研究将极大地加速该领域的新发现，包括为新疗法确定目标。
