title: ML372 blocks SMN ubiquitination and improves spinal muscular atrophy pathology in mice.
abstract: Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease and one of the leading inherited causes of infant mortality. SMA results from insufficient levels of the survival motor neuron (SMN) protein, and studies in animal models of the disease have shown that increasing SMN protein levels ameliorates the disease phenotype. Our group previously identified and optimized a new series of small molecules, with good potency and toxicity profiles and reasonable pharmacokinetics, that were able to increase SMN protein levels in SMA patient-derived cells. We show here that ML372, a representative of this series, almost doubles the half-life of residual SMN protein expressed from the SMN2 locus by blocking its ubiquitination and subsequent degradation by the proteasome. ML372 increased SMN protein levels in muscle, spinal cord, and brain tissue of SMA mice. Importantly, ML372 treatment improved the righting reflex and extended survival of a severe mouse model of SMA. These results demonstrate that slowing SMN degradation by selectively inhibiting its ubiquitination can improve the motor phenotype and lifespan of SMA model mice.
authors.affiliation: Department of Anatomy, Physiology and Genetics, Uniformed Services University of the Health Sciences, F. Edward Hebert School of Medicine, Bethesda, Maryland, USA.
authors.forename: Mahlet B
authors.initials: MB
authors.lastname: Abera
authors.affiliation: NIH Chemical Genomics Center, Discovery Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland, USA.
authors.forename: Jingbo
authors.initials: J
authors.lastname: Xiao
authors.affiliation: Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Nofziger
authors.affiliation: NIH Chemical Genomics Center, Discovery Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland, USA.
authors.forename: Steve
authors.initials: S
authors.lastname: Titus
authors.affiliation: NIH Chemical Genomics Center, Discovery Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland, USA.
authors.forename: Noel
authors.initials: N
authors.lastname: Southall
authors.affiliation: NIH Chemical Genomics Center, Discovery Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Zheng
authors.affiliation: Department of Anatomy, Physiology and Genetics, Uniformed Services University of the Health Sciences, F. Edward Hebert School of Medicine, Bethesda, Maryland, USA.
authors.forename: Kasey E
authors.initials: KE
authors.lastname: Moritz
authors.affiliation: NIH Chemical Genomics Center, Discovery Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland, USA.
authors.forename: Marc
authors.initials: M
authors.lastname: Ferrer
authors.affiliation: Department of Dermatology,, School of Medicine, Indiana University, Indianapolis, Indiana, USA.
authors.forename: Jonathan J
authors.initials: JJ
authors.lastname: Cherry
authors.affiliation: Department of Dermatology,, School of Medicine, Indiana University, Indianapolis, Indiana, USA.
authors.forename: Elliot J
authors.initials: EJ
authors.lastname: Androphy
authors.affiliation: NIH Chemical Genomics Center, Discovery Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland, USA.
authors.forename: Amy
authors.initials: A
authors.lastname: Wang
authors.affiliation: NIH Chemical Genomics Center, Discovery Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Xu
authors.affiliation: NIH Chemical Genomics Center, Discovery Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Austin
authors.affiliation: Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Kenneth H
authors.initials: KH
authors.lastname: Fischbeck
authors.affiliation: NIH Chemical Genomics Center, Discovery Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland, USA.
authors.forename: Juan J
authors.initials: JJ
authors.lastname: Marugan
authors.affiliation: Department of Anatomy, Physiology and Genetics, Uniformed Services University of the Health Sciences, F. Edward Hebert School of Medicine, Bethesda, Maryland, USA.
authors.forename: Barrington G
authors.initials: BG
authors.lastname: Burnett
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009134:Muscular Atrophy, Spinal / Q000188:drug therapy*; D055533:Survival of Motor Neuron 1 Protein / Q000737:chemistry*; D054875:Ubiquitination
chemical_list: D055533:Survival of Motor Neuron 1 Protein