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

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

doi:10.1172/jci.insight.88427

Cited by 16 publications

(15 citation statements)

References 47 publications

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“…To investigate whether the UBA1-dependent tRNA-synthetase GARS was being differentially ubiquitylated following modulation of UBA1 expression, a protein-specific ubiquitylation assay was performed. As the ubiquitylation pattern of SMN is well characterized ( Chang et al , 2004 ; Kwon et al , 2013 ; Abera et al , 2016 ), the ubiquitylation assay, in which the proteins of interest were co-transfected, was initially optimized using SMN, confirming the ubiquitylation pattern of SMN ( Supplementary Fig. 6 ).…”

Section: Resultsmentioning

confidence: 97%

UBA1/GARS-dependent pathways drive sensory-motor connectivity defects in spinal muscular atrophy

Shorrock

Hoorn

Boyd

et al. 2018

Brain

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Section: Resultsmentioning

confidence: 97%

UBA1/GARS-dependent pathways drive sensory-motor connectivity defects in spinal muscular atrophy

Shorrock

Hoorn

Boyd

et al. 2018

Brain

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“…Meanwhile, the SMNΔ7 fragment is polyubiquitinated and quickly degraded [ 186 ]. Pharmacological inhibition of ubiquitination of SMN, such as with the small molecule ML372, increased SMN protein levels and slowed disease progression of SMNΔ7 mice leading to longer survival, increased motor neuron size and less muscle atrophy [ 190 ]. When SMA-patient-derived fibroblasts were treated with salbutamol, the β 2 -adrenergic receptor agonist, there was also an increase in levels of SMN protein, possibly acting via activation of protein kinase A, thereby preventing SMN ubiquitination [ 191 ].…”

Section: Smn and Ubiquitin Pathwaysmentioning

confidence: 99%

“…Several E3 ubiquitin ligases have been shown to interact with SMN and so may be involved in its degradation through recruitment into the UPS. For example, Mindbomb 1 directly interacts with SMN [ 190 ]. Overexpression of Mindbomb 1 was shown to increase the amount of ubiquitinated SMN protein in cell culture, while a knockdown of Mindbomb 1 in the C. elegans model of SMA improves the SMN-deficient phenotype of defects in pharyngeal pumping [ 198 ].…”

Section: Smn and Ubiquitin Pathwaysmentioning

confidence: 99%

The role of survival motor neuron protein (SMN) in protein homeostasis

Chaytow

Huang

Gillingwater

et al. 2018

Cell. Mol. Life Sci.

150

115

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Ever since loss of survival motor neuron (SMN) protein was identified as the direct cause of the childhood inherited neurodegenerative disorder spinal muscular atrophy, significant efforts have been made to reveal the molecular functions of this ubiquitously expressed protein. Resulting research demonstrated that SMN plays important roles in multiple fundamental cellular homeostatic pathways, including a well-characterised role in the assembly of the spliceosome and biogenesis of ribonucleoproteins. More recent studies have shown that SMN is also involved in other housekeeping processes, including mRNA trafficking and local translation, cytoskeletal dynamics, endocytosis and autophagy. Moreover, SMN has been shown to influence mitochondria and bioenergetic pathways as well as regulate function of the ubiquitin–proteasome system. In this review, we summarise these diverse functions of SMN, confirming its key role in maintenance of the homeostatic environment of the cell.

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“…Preclinical studies indicate that several of these compounds can be highly effective in rescuing SMA phenotypes 81 . Other studies have attempted to increase SMN protein levels either by inhibiting histone deacytelases, increasing STAT5 activity or inhibiting SMN ubiquitination [82][83][84][85][86] , but although these approaches seemed to hold promise in early preclinical experiments, clinical studies so far have been disappointing [87][88][89] .…”

Section: Advances In Sma Therapy Developmentmentioning

confidence: 99%

Advances in therapy for spinal muscular atrophy: promises and challenges

2018

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Spinal muscular atrophy (SMA) is a devastating motor neuron disease that predominantly affects children and represents the most common cause of hereditary infant mortality. The condition results from deleterious variants in SMN1, which lead to depletion of the survival motor neuron protein (SMN). Now, 20 years after the discovery of this genetic defect, a major milestone in SMA and motor neuron disease research has been reached with the approval of the first disease-modifying therapy for SMA by US and European authorities - the antisense oligonucleotide nusinersen. At the same time, promising data from early-stage clinical trials of SMN1 gene therapy have indicated that additional therapeutic options are likely to emerge for patients with SMA in the near future. However, the approval of nusinersen has generated a number of immediate and substantial medical, ethical and financial implications that have the potential to resonate beyond the specific treatment of SMA. Here, we provide an overview of the rapidly evolving therapeutic landscape for SMA, highlighting current achievements and future opportunities. We also discuss how these developments are providing important lessons for the emerging second generation of combinatorial ('SMN-plus') therapies that are likely to be required to generate robust treatments that are effective across a patient's lifespan.

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

Cited by 16 publications

References 47 publications

UBA1/GARS-dependent pathways drive sensory-motor connectivity defects in spinal muscular atrophy

UBA1/GARS-dependent pathways drive sensory-motor connectivity defects in spinal muscular atrophy

The role of survival motor neuron protein (SMN) in protein homeostasis

Advances in therapy for spinal muscular atrophy: promises and challenges

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