ML372 blocks SMN ubiquitination and improves spinal muscular atrophy pathology in mice
| Autor: | Jonathan J. Cherry, Xin Xu, Elliot J. Androphy, Mahlet B. Abera, Christopher M. Austin, Wei Zheng, Juan J. Marugan, Jonathan H. Nofziger, Noel Southall, Jingbo Xiao, Barrington G. Burnett, Amy Wang, Kasey E. Moritz, Marc Ferrer, Kenneth H. Fischbeck, Steve Titus |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Male Neuromuscular disease Transgene animal diseases Mice Transgenic 030105 genetics & heredity Biology Muscular Atrophy Spinal 03 medical and health sciences Mice Ubiquitin medicine Animals Humans Ubiquitination General Medicine Spinal muscular atrophy Anatomy Motor neuron medicine.disease SMA Spinal cord Survival of Motor Neuron 1 Protein 3. Good health nervous system diseases Disease Models Animal 030104 developmental biology medicine.anatomical_structure HEK293 Cells Proteasome nervous system biology.protein Cancer research Research Article |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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