HuD interacts with survival motor neuron protein and can rescue spinal muscular atrophy-like neuronal defects
| Autor: | Janik Laframboise, Gabriel Sanchez, Janie Timbers, Hector Valderrama-Carvajal, Jocelyn Côté, Lisa Hubers |
|---|---|
| Rok vydání: | 2010 |
| Předmět: |
Protein-Arginine N-Methyltransferases
Tudor domain CARM1 Neurite Immunoblotting Fluorescent Antibody Technique Gene Expression Cell Cycle Proteins ELAV-Like Protein 4 Methylation Polymerase Chain Reaction Cell Line Muscular Atrophy Spinal Mice Neurites Genetics medicine Animals Protein Interaction Domains and Motifs Nerve Growth Factors RNA Messenger RNA Small Interfering Molecular Biology Genetics (clinical) Gene knockdown Base Sequence biology Cell Cycle Survival of motor neuron General Medicine Spinal muscular atrophy Anatomy Motor neuron medicine.disease Survival of Motor Neuron 1 Protein Cell biology Retinol-Binding Proteins Phenotype medicine.anatomical_structure ELAV Proteins nervous system Gene Knockdown Techniques Mutation biology.protein Signal Transduction Neurotrophin |
| Zdroj: | Human Molecular Genetics. 20:553-579 |
| ISSN: | 1460-2083 0964-6906 |
| DOI: | 10.1093/hmg/ddq500 |
| Popis: | Spinal muscular atrophy is an autosomal-recessive neuromuscular disease caused by disruption of the survival of motor neuron (SMN) gene, which promotes cytoplasmic assembly of the splicing core machinery. It remains unclear how a deficiency in SMN results in a disorder leading to selective degeneration of lower motor neurons. We report here that SMN interacts with RNA-binding protein HuD in neurites of motorneuron-derived MN-1 cells. This interaction is mediated through the Tudor domain of SMN and, importantly, naturally occurring Tudor mutations found in patients with severe spinal muscular atrophy (SMA) completely abrogate the interaction, underscoring its relevance to the disease process. We also characterized a regulatory pathway involving coactivator-associated arginine methyltransferase 1 (CARM1) and HuD. Specifically, we show that CARM1 expression is rapidly downregulated, at the protein level, following induction of differentiation through retinoid and neurotrophic signaling. Using purified proteins, we demonstrate that methylation of HuD by CARM1 reduces its interaction with the p21(cip1/waf1) mRNA, showing that CARM1 can directly influence RNA-binding activity. We further demonstrate that this CARM1-dependent regulatory switch mainly controls the activity of HuD in promoting cell-cycle exit, whereas the interaction between HuD and SMN is required for proper recruitment of HuD and its mRNA targets in neuronal RNA granules. Finally, we were able to rescue SMA-like defects in a hypomorphic Smn knockdown MN-1 cell line through overexpression of HuD. Together, these findings extend our understanding of specific role(s) of SMN in motor neurons and provide crucial insights into potential new avenues for SMA therapeutic strategies. |
| Databáze: | OpenAIRE |
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