Decreased number of Gemini of coiled bodies and U12 snRNA level in amyotrophic lateral sclerosis.

Abstract

Disappearance of TAR-DNA-binding protein 43 kDa (TDP-43) from the nucleus contributes to the pathogenesis of amyotrophic lateral sclerosis (ALS), but the nuclear function of TDP-43 is not yet fully understood. TDP-43 associates with nuclear bodies including Gemini of coiled bodies (GEMs). GEMs contribute to the biogenesis of uridine-rich small nuclear RNA (U snRNA), a component of splicing machinery. The number of GEMs and a subset of U snRNAs decrease in spinal muscular atrophy, a lower motor neuron disease, suggesting that alteration of U snRNAs may also underlie the molecular pathogenesis of ALS. Here, we investigated the number of GEMs and U11/12-type small nuclear ribonucleoproteins (snRNP) by immunohistochemistry and the level of U snRNAs using real-time quantitative RT-PCR in ALS tissues. GEMs decreased in both TDP-43-depleted HeLa cells and spinal motor neurons in ALS patients. Levels of several U snRNAs decreased in TDP-43-depleted SH-SY5Y and U87-MG cells. The level of U12 snRNA was decreased in tissues affected by ALS (spinal cord, motor cortex and thalamus) but not in tissues unaffected by ALS (cerebellum, kidney and muscle). Immunohistochemical analysis revealed the decrease in U11/12-type snRNP in spinal motor neurons of ALS patients. These findings suggest that loss of TDP-43 function decreases the number of GEMs, which is followed by a disturbance of pre-mRNA splicing by the U11/U12 spliceosome in tissues affected by ALS.

• Authors: Tomohiko Ishihara, Yuko Ariizumi, Atsushi Shiga, Taisuke Kato, Chun-Feng Tan, Tatsuya Sato, Yukari Miki, Mariko Yokoo, Takeshi Fujino, Akihide Koyama, Akio Yokoseki, Masatoyo Nishizawa, Akiyoshi Kakita, Hitoshi Takahashi, Osamu Onodera
• Journal: Human molecular genetics (Hum Mol Genet) Vol. 22 Issue 20 Pg. 4136-47 (Oct 15 2013) ISSN: 1460-2083 [Electronic] England
• PMID: 23740936 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• DNA-Binding Proteins
• RNA, Small Nuclear
• Ribonucleoproteins, Small Nuclear
• SMN Complex Proteins
• U11-U12 small nuclear ribonucleoprotein
• U12 small nuclear RNA

Topics

• Amyotrophic Lateral Sclerosis (genetics, metabolism, pathology)
• Cells, Cultured
• DNA-Binding Proteins (genetics, metabolism)
• Gemini of Coiled Bodies (metabolism)
• HeLa Cells
• Humans
• Motor Cortex (metabolism, pathology)
• Motor Neurons (metabolism, pathology)
• RNA Splicing
• RNA, Small Nuclear (genetics, metabolism)
• Real-Time Polymerase Chain Reaction
• Ribonucleoproteins, Small Nuclear (genetics, metabolism)
• SMN Complex Proteins (genetics, metabolism)
• Spinal Cord (metabolism, pathology)
• Thalamus (metabolism, pathology)