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: Since an abnormal disappearance of TDP-43 from nuclei was observed in motor neurons from sporadic ALS patients and Gems were lost in these neurons (Fig 3) and TDP-43 was important for maintaining the proper integrity of spliceosome U snRNPs (Fig 4), we thought it would be of high interest to investigate whether U snRNA and U snRNP misregulation occurs in affected regions of ALS patients. Frozen cervical spinal cords from four sporadic ALS patients, with spinal cords from five other neurological disease patients serving as controls, were analysed for levels of U snRNAs and other mRNAs. Detailed clinical information is listed in Supporting Information Table S1. Almost all U snRNAs were upregulated in the spinal cords of ALS patients when compared with the control spinal cords (Fig 5A and B). This result confirms that the misregulation of U snRNA levels occurs in the affected region of ALS patients.
Affiliation: Laboratory for Motor Neuron Disease, RIKEN Brain Science Institute, Wako, Saitama, Japan. firstname.lastname@example.org