SMA-linked SMN mutants prevent phase separation properties and SMN interactions with FMRP family members

Author:

Binda Olivier12ORCID,Juillard Franceline1,Ducassou Julia Novion3,Kleijwegt Constance14ORCID,Paris Geneviève2,Didillon Andréanne2,Baklouti Faouzi1ORCID,Corpet Armelle1ORCID,Couté Yohann3ORCID,Côté Jocelyn2,Lomonte Patrick1ORCID

Affiliation:

1. Université Claude Bernard Lyon 1, CNRS UMR 5261, INSERM U1315, LabEx DEV2CAN, Institut NeuroMyoGène-Pathophysiology and Genetics of Neuron and Muscle, Team Chromatin Dynamics, Nuclear Domains, Virus, Lyon, France

2. University of Ottawa, Faculty of Medicine, Department of Cellular and Molecular Medicine, Ottawa, Canada

3. Université Grenoble Alpes, INSERM, CEA, UMR BioSanté U1292, CNRS, CEA, FR2048, Grenoble, France

4. Université de Montpellier, CNRS UMR 9002, Institut de Génétique Humaine, Montpellier, France

Abstract

Although recent advances in gene therapy provide hope for spinal muscular atrophy (SMA) patients, the pathology remains the leading genetic cause of infant mortality. SMA is a monogenic pathology that originates from the loss of theSMN1gene in most cases or mutations in rare cases. Interestingly, severalSMN1mutations occur within the TUDOR methylarginine reader domain of SMN. We hypothesized that inSMN1mutant cases, SMA may emerge from aberrant protein-protein interactions between SMN and key neuronal factors. Using a BioID proteomic approach, we have identified and validated a number of SMN-interacting proteins, including fragile X mental retardation protein (FMRP) family members (FMRFM). Importantly, SMA-linked SMNTUDORmutant forms (SMNST) failed to interact with FMRFM. In agreement with the recent work, we define biochemically that SMN forms droplets in vitro and these droplets are stabilized by RNA, suggesting that SMN could be involved in the formation of membraneless organelles, such as Cajal nuclear bodies. Finally, we found that SMN and FMRP co-fractionate with polysomes, in an RNA-dependent manner, suggesting a potential role in localized translation in motor neurons.

Funder

Agence Nationale de la Recherche

Canadian Institutes of Health Research

AFM-Téléthon

Publisher

Life Science Alliance, LLC

Subject

Health, Toxicology and Mutagenesis,Plant Science,Biochemistry, Genetics and Molecular Biology (miscellaneous),Ecology

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