Two motor neuron diseases, amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA), are caused by distinct genes involved in RNA metabolism, TDP-43 and FUS/TLS, and SMN, respectively. However, whether there is a shared defective mechanism in RNA metabolism common to these two diseases remains unclear. Here, we show that TDP-43 and FUS/TLS localize in nuclear Gems through an association with SMN, and that all three proteins function in spliceosome maintenance. We also show that in ALS, Gems are lost, U snRNA levels are up-regulated and spliceosomal U snRNPs abnormally and extensively accumulate in motor neuron nuclei, but not in the temporal lobe of FTLD with TDP-43 pathology. This aberrant accumulation of U snRNAs in ALS motor neurons is in direct contrast to SMA motor neurons, which show reduced amounts of U snRNAs, while both have defects in the spliceosome. These findings indicate that a profound loss of spliceosome integrity is a critical mechanism common to neurodegeneration in ALS and SMA, and may explain cell-type specific vulnerability of motor neurons. This paper reveals the importance of nuclear Gems and spliceosomal U snRNPs in motor neuron survival common to ALS and SMA. © 2013 The Authors. Published by John Wiley and Sons, Ltd on behalf of EMBO.
Tsuiji, H., Iguchi, Y., Furuya, A., Kataoka, A., Hatsuta, H., Atsuta, N., … Yamanaka, K. (2013). Spliceosome integrity is defective in the motor neuron diseases ALS and SMA. EMBO Molecular Medicine, 5(2), 221–234. https://doi.org/10.1002/emmm.201202303