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

EMBO Molecular Medicine

Hitomi Tsuiji³  Yohei Iguchi¹  Asako Furuya⁴  Ayane Kataoka⁴  Hiroyuki Hatsuta²  Naoki Atsuta¹  Fumiaki Tanaka¹  Yoshio Hashizume⁵  Hiroyasu Akatsu⁶  Shigeo Murayama²  Gen Sobue¹ 

[1] Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan;Department of Neuropathology, Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, Itabashi, Tokyo, Japan;E-mail address: 关键词: ALS;    SMN;    snRNA;    Spliceosome;    TDP‐43;   

DOI  :  10.1002/emmm.201202303

来源: Wiley

【 摘 要 】

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.

【 授权许可】

CC BY   
Copyright © 2013 EMBO Molecular Medicine

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