Sanelli Teresa, Xiao Shangxi, Horne Patrick, Bilbao Juan, Zinman Lorne, Robertson Janice
Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario, Canada.
J Neuropathol Exp Neurol. 2007 Dec;66(12):1147-53. doi: 10.1097/nen.0b013e31815c5edd.
Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease characterized by the presence of various types of ubiquitinated inclusions in the cytoplasm of affected motor neurons. The identification of the ubiquitinated targets within these inclusions has represented a major challenge, as this may provide new gene candidates and/or clues to understanding the neurodegenerative mechanism(s) underlying the disease. As such, the nuclear factor TAR DNA-binding protein (TDP-43) was recently identified as a component of ubiquitinated skein-like inclusions and round inclusions in ALS. This identification combined with biochemical evidence led to the suggestion that TDP-43 is the key ubiquitinated target and major disease protein in ALS. Here, using 3-dimensional deconvolution imaging, we have obtained remarkable resolution of skein-like inclusions and round inclusions in ALS. Surprisingly we have found that in contrast to current thinking, TDP-43 is not the major ubiquitinated target within these types of inclusions. These findings raise the possibility that TDP-43 may not necessarily be the key disease protein in ALS and indicate that the major target(s) of ubiquitination remain to be identified.
肌萎缩侧索硬化症（ALS）是一种成年发病的神经退行性疾病，其特征是在受影响的运动神经元细胞质中存在各种类型的泛素化包涵体。确定这些包涵体内的泛素化靶点是一项重大挑战，因为这可能提供新的基因候选物和/或有助于理解该疾病潜在神经退行性机制的线索。因此，核因子TAR DNA结合蛋白（TDP - 43）最近被确定为ALS中泛素化的绞丝状包涵体和圆形包涵体的一个组成部分。这一发现与生化证据相结合，表明TDP - 43是ALS中关键的泛素化靶点和主要疾病蛋白。在此，我们使用三维去卷积成像技术，获得了ALS中绞丝状包涵体和圆形包涵体的高分辨率图像。令人惊讶的是，我们发现与目前的认识相反，TDP - 43并不是这些类型包涵体内主要的泛素化靶点。这些发现增加了TDP - 43不一定是ALS关键疾病蛋白的可能性，并表明泛素化的主要靶点仍有待确定。
