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. email@example.comShow MeSH
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Mentions: To identify the region within TDP-43 that is required for localization to Gems, we performed domain analysis using deletion mutants of TDP-43 (Fig 2A). Our analysis revealed that the C-terminus of TDP-43, where several known ALS-linked mutations are located, was responsible for the proper localization to Gems (Fig 2B and Supporting Information Fig S3). More specifically, amino acids 321–366 of the C-terminus, which interact with hnRNP A2 (D'Ambrogio et al, 2009), were important for localization to Gems (Fig 2B). Furthermore, the RNA-binding activity of TDP-43 is partially required, as both RNA-recognition motif 1 (RRM1) deletion mutants and F147L/F149L double point mutants had reduced localizations to Gems (Fig 2B). These results indicate that protein–protein interactions mediated by the latter half of the C-terminal region and the RNA binding activity play critical roles in the proper localization of TDP-43 to Gems.
Affiliation: Laboratory for Motor Neuron Disease, RIKEN Brain Science Institute, Wako, Saitama, Japan. firstname.lastname@example.org