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ML372 blocks SMN ubiquitination and improves spinal muscular atrophy pathology in mice
Mahlet B. Abera, … , Juan J. Marugan, Barrington G. Burnett
Mahlet B. Abera, … , Juan J. Marugan, Barrington G. Burnett
Published November 17, 2016
Citation Information: JCI Insight. 2016;1(19):e88427. https://doi.org/10.1172/jci.insight.88427.
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Research Article Cell biology Therapeutics

ML372 blocks SMN ubiquitination and improves spinal muscular atrophy pathology in mice

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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

Mahlet B. Abera, Jingbo Xiao, Jonathan Nofziger, Steve Titus, Noel Southall, Wei Zheng, Kasey E. Moritz, Marc Ferrer, Jonathan J. Cherry, Elliot J. Androphy, Amy Wang, Xin Xu, Christopher Austin, Kenneth H. Fischbeck, Juan J. Marugan, Barrington G. Burnett

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Figure 1

ML372 enhances SMN protein level and function.

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ML372 enhances SMN protein level and function.
Spinal muscular atrophy p...
Spinal muscular atrophy patient fibroblast 3813 cells were treated with vehicle or ML372 at indicated concentrations for 48 hours. (A) SMN2 transcript expression was measured by qPCR. (B) The relative ratio of full-length SMN to the Δ7 mutant (FL/Δ7) was used to determine the exon 7 inclusion in SMN2 mRNA. (C) Western blot was used to determined SMN protein levels (left panel). Densitometry analysis is shown as the mean ± SEM (n = 3, **P < 0.01, ***P < 0.001) (right panel). (D) A series of wash-out experiments were performed and SMN protein level was determined by Western blot. Densitometry analysis is shown as the mean ± SEM (n = 3, *P < 0.05, **P < 0.01) (right panel). All P values determined by unpaired 2-tailed Student’s t test.

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