Spliceosome integrity is defective in the motor neuron diseases ALS and SMA.
Bottom Line: 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.
Affiliation: Laboratory for Motor Neuron Disease, RIKEN Brain Science Institute, Wako, Saitama, Japan. firstname.lastname@example.orgShow MeSH
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Mentions: TDP-43 is an RNA-binding protein that predominantly localizes to the nucleus and regulates pre-mRNA splicing together with SR proteins or with other RNA-binding proteins such as hnRNPA2. The regulation of pre-mRNA is spatially and temporally controlled by splicing factors such as SR proteins that concentrate in nuclear speckles (Kumaran et al, 2008), suggesting that TDP-43 localizes to nuclear speckles as well as nucleoplasm. However, sub-nuclear localization of TDP-43 has been debated (Casafont et al, 2009; Fiesel et al, 2010; Shan et al, 2010; Wang et al, 2002). Our detailed analysis of sub-nuclear TDP-43 distribution revealed that TDP-43 was concentrated in Gems, which are marked by survival of motor neuron (SMN; Fig 1A, arrows) or Gemin8 (Fig 1B, arrows); Cajal bodies, which are marked by Coilin (Fig 1C, arrows); and paraspeckles, which are marked by p54nrb (Supporting Information Fig S1A, arrows). TDP-43 was partially overlapped with the SR protein SRSF2/SC35 in nuclear speckles (Supporting Information Fig S1B, arrows), and was not concentrated in PML bodies, the nucleolus, or SAM bodies (Supporting Information Fig S1C–E). TDP-43 was also localized to Gems in the neuronal cell line SH-SY5Y and in primary cultured neurons from mouse hippocampus (Fig 1D and E). FUS/TLS, an ALS-causative protein, was also localized to Gems in Hela cells (data not shown) and in primary cultured neurons from mouse hippocampus (Fig 1F). This is consistent given the known interaction of TDP-43 and FUS. Therefore, it is evident that both TDP-43 and FUS, RNA binding proteins of which mutations cause ALS, colocalize to Gems along with SMN.
Affiliation: Laboratory for Motor Neuron Disease, RIKEN Brain Science Institute, Wako, Saitama, Japan. email@example.com