Spliceosome integrity is defective in the motor neuron diseases ALS and SMA

Autor: Hitomi Tsuiji, Yohei Iguchi, Asako Furuya, Ayane Kataoka, Hiroyuki Hatsuta, Naoki Atsuta, Fumiaki Tanaka, Yoshio Hashizume, Hiroyasu Akatsu, Shigeo Murayama, Gen Sobue, Koji Yamanaka
Jazyk: angličtina
Rok vydání: 2013
Předmět:
Zdroj: EMBO Molecular Medicine, Vol 5, Iss 2, Pp 221-234 (2013)
Druh dokumentu: article
ISSN: 20120230
1757-4676
1757-4684
DOI: 10.1002/emmm.201202303
Popis: 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.
Databáze: Directory of Open Access Journals
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