title: Spliceosome integrity is defective in the motor neuron diseases ALS and SMA.
abstract: 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.
authors.affiliation: Laboratory for Motor Neuron Disease, RIKEN Brain Science Institute, Wako, Saitama, Japan. hitomitsuiji@brain.riken.jp
authors.forename: Hitomi
authors.initials: H
authors.lastname: Tsuiji
authors.forename: Yohei
authors.initials: Y
authors.lastname: Iguchi
authors.forename: Asako
authors.initials: A
authors.lastname: Furuya
authors.forename: Ayane
authors.initials: A
authors.lastname: Kataoka
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Hatsuta
authors.forename: Naoki
authors.initials: N
authors.lastname: Atsuta
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Tanaka
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Hashizume
authors.forename: Hiroyasu
authors.initials: H
authors.lastname: Akatsu
authors.forename: Shigeo
authors.initials: S
authors.lastname: Murayama
authors.forename: Gen
authors.initials: G
authors.lastname: Sobue
authors.forename: Koji
authors.initials: K
authors.lastname: Yamanaka
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009046:Motor Neurons / Q000378:metabolism; D009134:Muscular Atrophy, Spinal / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D012342:RNA, Small Nuclear / Q000235:genetics / Q000378:metabolism; D034702:RNA-Binding Protein FUS / Q000235:genetics / Q000378:metabolism; D055532:SMN Complex Proteins / Q000235:genetics / Q000378:metabolism; D017381:Spliceosomes / Q000235:genetics / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D012342:RNA, Small Nuclear; D034702:RNA-Binding Protein FUS; D055532:SMN Complex Proteins