Interaction of AAA chaperones with amyloid fibrils related to human diseases

TDP-43的淀粉样纤维在由AAA伴侣VCP突变引起的神经退行性疾病患者中积聚。生化和高速原子力显微镜证实了VCP与TDP-43淀粉样纤维的特异性相互作用。与疾病相关的突变减少了VCP和TDP-43淀粉样纤维之间的相互作用。VCP显示，在ATP存在下，TDP-43淀粉样纤维具有显著的解聚活性。高速AFM分析表明，线虫VCP同源物CDC-48的N-D1环重复顺时针旋转并相对于D2环复位。人的VCP也得到了类似的结果。基于这些观察结果，我们提出了VCP的反复前后旋转可能解释了解聚中的机械力。

Amyloid fibrils of TDP-43 accumulate in patients of neurodegenerative diseases caused by mutations in the AAA chaperone VCP. Specific interaction of VCP with TDP-43 amyloid fibrils was demonstrated biochemically and by high-speed atomic force microscopy. Disease-related mutations reduced interaction between VCP and TDP-43 amyloid fibrils. VCP showed a significant disaggregation activity of TDP-43 amyloid fibrils in the presence of ATP. High-speed AFM analysis revealed that the N-D1 ring of CDC-48, a C. elegans VCP homolog, repeatedly rotates clockwise and resets against the D2 ring. A similar result was obtained with human VCP. Based on these observations, we have proposed that repeated back and forward rotations of VCP may account for mechanical force in disaggregation.