title: Dynamics of survival of motor neuron (SMN) protein interaction with the mRNA-binding protein IMP1 facilitates its trafficking into motor neuron axons.
abstract: Spinal muscular atrophy (SMA) is a lethal neurodegenerative disease specifically affecting spinal motor neurons. SMA is caused by the homozygous deletion or mutation of the survival of motor neuron 1 (SMN1) gene. The SMN protein plays an essential role in the assembly of spliceosomal ribonucleoproteins. However, it is still unclear how low levels of the ubiquitously expressed SMN protein lead to the selective degeneration of motor neurons. An additional role for SMN in the regulation of the axonal transport of mRNA-binding proteins (mRBPs) and their target mRNAs has been proposed. Indeed, several mRBPs have been shown to interact with SMN, and the axonal levels of few mRNAs, such as the β-actin mRNA, are reduced in SMA motor neurons. In this study we have identified the β-actin mRNA-binding protein IMP1/ZBP1 as a novel SMN-interacting protein. Using a combination of biochemical assays and quantitative imaging techniques in primary motor neurons, we show that IMP1 associates with SMN in individual granules that are actively transported in motor neuron axons. Furthermore, we demonstrate that IMP1 axonal localization depends on SMN levels, and that SMN deficiency in SMA motor neurons leads to a dramatic reduction of IMP1 protein levels. In contrast, no difference in IMP1 protein levels was detected in whole brain lysates from SMA mice, further suggesting neuron specific roles of SMN in IMP1 expression and localization. Taken together, our data support a role for SMN in the regulation of mRNA localization and axonal transport through its interaction with mRBPs such as IMP1.
authors.affiliation: Department of Cell Biology, Emory University School of Medicine, Atlanta, GA 30322, USA.|Department of Neurology, UMASS Medical School, Worcester, MA 01605, USA.
authors.forename: Claudia
authors.initials: C
authors.lastname: Fallini
authors.affiliation: Department of Cell Biology, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Jeremy P
authors.initials: JP
authors.lastname: Rouanet
authors.affiliation: Department of Cell Biology, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Paul G
authors.initials: PG
authors.lastname: Donlin-Asp
authors.affiliation: Department of Cell Biology, Emory University School of Medicine, Atlanta, GA 30322, USA.|Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Peng
authors.initials: P
authors.lastname: Guo
authors.affiliation: Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Honglai
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Singer
authors.affiliation: Department of Cell Biology, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Wilfried
authors.initials: W
authors.lastname: Rossoll
authors.affiliation: Department of Cell Biology, Emory University School of Medicine, Atlanta, GA 30322, USA.|Department of Neurology and Center for Neurodegenerative Diseases, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Gary J
authors.initials: GJ
authors.lastname: Bassell
mesh_terms: D000818:Animals; D001370:Axonal Transport; D001369:Axons / Q000378:metabolism*; D001693:Biological Transport, Active; D001921:Brain / Q000378:metabolism; D002478:Cells, Cultured; D002837:Chromaffin Granules / Q000378:metabolism; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000378:metabolism*; D054730:Protein Interaction Domains and Motifs; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D055533:Survival of Motor Neuron 1 Protein / Q000235:genetics / Q000378:metabolism*; D055540:Survival of Motor Neuron 2 Protein / Q000235:genetics
chemical_list: C498634:Igf2bp1 protein, rat; D016601:RNA-Binding Proteins; C526477:SMN2 protein, human; C526472:Smn1 protein, mouse; D055533:Survival of Motor Neuron 1 Protein; D055540:Survival of Motor Neuron 2 Protein
keywords: IMP1; SMA; SMN; axon; mRNA binding proteins
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