Alami, N.H., Smith, R.B., Carrasco, M.A., Williams, L.A., Winborn, C.S., Han, S.S., Kiskinis, E., Winborn, B., Freibaum, B.D., Kanagaraj, A., Clare, A.J., Badders, N.M., Bilican, B., Chaum, E., Chandran, S., Shaw, C.E., Eggan, K.C., Maniatis, T., Taylor, J.P. (2014). Axonal transport of TDP-43 mRNA granules is impaired by ALS-causing mutations.  Neuron 81(3): 536--543.

FBrf0224596

Research paper

The RNA-binding protein TDP-43 regulates RNA metabolism at multiple levels, including transcription, RNA splicing, and mRNA stability. TDP-43 is a major component of the cytoplasmic inclusions characteristic of amyotrophic lateral sclerosis and some types of frontotemporal lobar degeneration. The importance of TDP-43 in disease is underscored by the fact that dominant missense mutations are sufficient to cause disease, although the role of TDP-43 in pathogenesis is unknown. Here we show that TDP-43 forms cytoplasmic mRNP granules that undergo bidirectional, microtubule-dependent transport in neurons in vitro and in vivo and facilitate delivery of target mRNA to distal neuronal compartments. TDP-43 mutations impair this mRNA transport function in vivo and in vitro, including in stem cell-derived motor neurons from ALS patients bearing any one of three different TDP-43 ALS-causing mutations. Thus, TDP-43 mutations that cause ALS lead to partial loss of a novel cytoplasmic function of TDP-43.

PMC3939050 (PMC) (EuropePMC)