筋萎縮性側索硬化症（ALS）病原蛋白質の局在に基づく抗体医療戦略

抄録

Protein misfolding underlies the molecular basis of amyotrophic lateral sclerosis (ALS) of either sporadic or familial cases. TAR DNA–binding protein 43kDa (TDP–43) is a pathogenic protein in most sporadic ALS, in which aberrantly mislocalized species disrupt the homeostasis of RNA metabolism and protein quality control. In Japan, the mutation in superoxide dismutase 1 (SOD1) is the most prevalent genetic cause in familial ALS, in which the gain of toxic function is implicated in the pathogenesis. We have successfully generated monoclonal antibodies against misfolded forms of TDP–43 or mutant SOD1 proteins exclusively as a tool for molecular targeting of these pathogenic proteins. For TDP–43 in ALS, we constructed short–chain variable fragments (scFv) for intrabody with proteolytic signals, to eliminate the immunocomplex in the proteasome or autophagosome. Autolytic intrabody eliminated TDP–43 aggregates and prevented cell death caused by TDP aggregates in vitro and in the utero–transporated pup brain.

On the other hand, a misfolded–specific monoclonal antibody against SOD1 was introduced intrathecally to capture extracellular species to prevent cell to cell propagation or inhibit microglial activation, resulting in the significant prolongation of the longevity of the mutant SOD1 transgenic rat. Immunotherapy is a promising strategy for protein misfolding diseases such as ALS. However, the immunization approaches should be cautiously considered depending on the site of pathogenic proteins inside or outside motor neurons.