PURPOSE: While abnormal deposition of TDP-43 is a hallmark in neurons of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitin-positive inclusion bodies (FTLD-U), the pathogenic mechanism of the diseases by TDP-43 is largely unknown. TDP-43 is an RNA-binding protein that supposedly regulates transcription, splicing, nucleocytoplasmic export and transport of mRNA. We hypothesized that the failure of mRNA transport to axons by TDP-43 is associated with neurodegeneration in ALS and FTLD-U, and aimed to clarify the function of TDP-43 by identifying the target mRNA for TDP-43-mediated axonal transport.
METHODS: We detected mRNA decreased by shRNA-based TDP-43 down-regulation in axons of embryonic mouse cortical neurons using microarray analysis. We next analyzed the identified mRNA for binding and transport with TDP-43, localization, translation and function in axons.
RESULTS: Down-regulation of TDP-43 expression decreased mRNA of ribosomal proteins in axons. TDP-43 binds and transports the mRNA through their untranslated region. These mRNA were translated locally, and overall ribosomal function was suppressed in axons by the decreased expression of TDP-43.
DISCUSSION: In ALS and FTLD-U, neurodegeneration can arise from impaired protein synthesis in axons as a result of aggregation-mediated deficiency of transport of ribosomal protein mRNA by TDP-43. Further analysis will clarify the detailed molecular mechanisms.