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

被引：158

作者：

Tsuiji, Hitomi ^{[1
]}

Iguchi, Yohei ^{[2
]}

Furuya, Asako ^{[1
]}

Kataoka, Ayane ^{[1
]}

Hatsuta, Hiroyuki ^{[3
,4
]}

Atsuta, Naoki ^{[2
]}

Tanaka, Fumiaki ^{[2
]}

Hashizume, Yoshio ^{[5
]}

Akatsu, Hiroyasu ^{[6
]}

Murayama, Shigeo ^{[3
,4
]}

Sobue, Gen ^{[2
,7
]}

Yamanaka, Koji ^{[1
,7
,8
,9
]}

机构：

[1] RIKEN, Lab Motor Neuron Dis, Brain Sci Inst, Wako, Saitama, Japan

[2] Nagoya Univ, Grad Sch Med, Dept Neurol, Nagoya, Aichi 4648601, Japan

[3] Tokyo Metropolitan Geriatr Hosp, Dept Neuropathol, Itabashi Ku, Tokyo 173, Japan

[4] Inst Gerontol, Itabashi Ku, Tokyo, Japan

[5] Fukushimura Hosp, Dept Neuropathol, Toyohashi, Aichi, Japan

[6] Fukushimura Hosp, Choju Med Inst, Toyohashi, Aichi, Japan

[7] Japan Sci & Technol Agcy, CREST, Kawaguchi, Saitama, Japan

[8] Saitama Univ, Brain Sci Inst, Saitama 3388570, Japan

[9] Kyoto Univ, Grad Sch Med, Kyoto, Japan

来源：

EMBO MOLECULAR MEDICINE | 2013年 / 5卷 / 02期

关键词：

ALS; SMN; snRNA; Spliceosome; TDP-43; SPINAL MUSCULAR-ATROPHY; FRONTOTEMPORAL LOBAR DEGENERATION; AMYOTROPHIC-LATERAL-SCLEROSIS; RNA TARGETS; SMN1; GENE; PROTEIN; TDP-43; SURVIVAL; BINDING; DEFICIENCY;

D O I：

10.1002/emmm.201202303

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

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.

引用

页码：221 / 234

页数：14