Journal
EMBO MOLECULAR MEDICINE
Volume 5, Issue 2, Pages 221-234Publisher
WILEY
DOI: 10.1002/emmm.201202303
Keywords
ALS; SMN; snRNA; Spliceosome; TDP-43
Categories
Funding
- Ministry for Education, Culture, and Sports, Science and Technology of Japan [23111006, 23110523, 23700455]
- Research Committee of CNS Degenerative Diseases, the Ministry of Health, Labor and Welfare of Japan
- National Center for Geriatrics and Gerontology, Japan [22-14]
- Grants-in-Aid for Scientific Research [23700455, 22129005, 24700371, 24500431] Funding Source: KAKEN
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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.
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