Ubiquitin carboxyl-terminal hydrolase L1 (UCHL1) regulates the level of SMN expression through ubiquitination in primary spinal muscular atrophy fibroblasts

Hsu, Shih-Hsien; Lai, Ming-Chi; Er, Tze‐Kiong; Yang, San‐Nan; Hung, Chih‐Hsing; Tsai, Hsin-Hung; Lin, Yan Ren; Chang, Jan-Gowth; Lo, Yi-Ching; Jong, Yuh‐Jyh

doi:10.1016/j.cca.2010.07.035

Cited by 39 publications

(45 citation statements)

References 43 publications

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“…Our finding that loss of UBA1 protein in SMA likely resulted from perturbations to both Uba1 mRNA missplicing and disruption to physical interactions between SMN and UBA1 as well as modifications to normal postnatal subcellular redistribution of the protein suggests that molecular pathways responsible for controlling UBA1 levels in vivo are complex and multifaceted. However, the demonstration of interactions between UBA1 and SMN provides additional evidence to support the hypothesis that interactions between SMN and ubiquitination pathways are key for the normal form and function of the neuromuscular system, not only with regards to the regulation of SMN protein stability (28)(29)(30), but also with respect to modulating ubiquitin homeostasis and cell viability.…”

Section: Micementioning

confidence: 78%

“…Although it is known that SMN protein interacts with the ubiquitinproteasome system in order to regulate its own stability (28)(29)(30), our study markedly extends our understanding of the importance of these interactions to include a direct role for dysregulation of ubiquitin homeostasis in the pathogenesis of SMA. When taken together with human genetic data showing that mutations in UBA1 cause pathological changes similar to those found in SMN-dependent SMA (22), our findings suggest that perturbations in ubiquitin homeostasis, and UBA1 in particular, may represent a common molecular pathway underlying neuromuscular pathology across genetically distinct forms of the disease.…”

Section: Micementioning

confidence: 79%

“…Ubiquitination pathways, and UBA1 in particular, were of interest in the context of SMA because mutations in the gene coding for human UBA1 (UBE1) are sufficient to cause a genetically distinct form of the disease, known as X-linked infantile SMA (22). Moreover, ubiquitination pathways are known to regulate axonal and synaptic stability (27) as well as the stability and degradation of the SMN protein itself (28)(29)(30).…”

Section: Widespread Perturbations In Ubiquitin Homeostasis In Animal mentioning

confidence: 99%

“…As mRNA levels for Uba1 remained unchanged in the spinal cords of SMA mice (Figure 2A), it was unlikely that UBA1 protein levels were reduced as a result of global deficiencies in transcription of Uba1 mRNA. Given that SMN protein interacts with other proteins in vitro, including members of the ubiquitin-proteasome sys- tem such as UCHL1 (29,30), we next wanted to determine whether SMN could be influencing UBA1 levels as a result of direct physical interactions in vivo. We therefore performed coimmunoprecipitation (co-IP) experiments on spinal cord extracts from WT mice, using anti-SMN beads.…”

Section: Smn-uba1 Interactions and Dysregulation Of Uba1 Splicing In mentioning

confidence: 99%

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Dysregulation of ubiquitin homeostasis and β-catenin signaling promote spinal muscular atrophy

Wishart¹,

Mutsaers²,

Rießland³

et al. 2014

J. Clin. Invest.

157

253

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The autosomal recessive neurodegenerative disease spinal muscular atrophy (SMA) results from low levels of survival motor neuron (SMN) protein; however, it is unclear how reduced SMN promotes SMA development. Here, we determined that ubiquitin-dependent pathways regulate neuromuscular pathology in SMA. Using mouse models of SMA, we observed widespread perturbations in ubiquitin homeostasis, including reduced levels of ubiquitin-like modifier activating enzyme 1 (UBA1). SMN physically interacted with UBA1 in neurons, and disruption of Uba1 mRNA splicing was observed in the spinal cords of SMA mice exhibiting disease symptoms. Pharmacological or genetic suppression of UBA1 was sufficient to recapitulate an SMAlike neuromuscular pathology in zebrafish, suggesting that UBA1 directly contributes to disease pathogenesis. Dysregulation of UBA1 and subsequent ubiquitination pathways led to β-catenin accumulation, and pharmacological inhibition of β-catenin robustly ameliorated neuromuscular pathology in zebrafish, Drosophila, and mouse models of SMA. UBA1-associated disruption of β-catenin was restricted to the neuromuscular system in SMA mice; therefore, pharmacological inhibition of β-catenin in these animals failed to prevent systemic pathology in peripheral tissues and organs, indicating fundamental molecular differences between neuromuscular and systemic SMA pathology. Our data indicate that SMA-associated reduction of UBA1 contributes to neuromuscular pathogenesis through disruption of ubiquitin homeostasis and subsequent β-catenin signaling, highlighting ubiquitin homeostasis and β-catenin as potential therapeutic targets for SMA.

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Section: Micementioning

confidence: 78%

Section: Micementioning

confidence: 79%

Section: Widespread Perturbations In Ubiquitin Homeostasis In Animal mentioning

confidence: 99%

Section: Smn-uba1 Interactions and Dysregulation Of Uba1 Splicing In mentioning

confidence: 99%

See 2 more Smart Citations

Dysregulation of ubiquitin homeostasis and β-catenin signaling promote spinal muscular atrophy

Wishart¹,

Mutsaers²,

Rießland³

et al. 2014

J. Clin. Invest.

157

253

View full text Add to dashboard Cite

show abstract

“…Consistently, restoration of UBA1 has been recently shown to ameliorate disease pathology in zebrafish and mouse models of SMA (19). Ubiquitination pathways regulate axonal and synaptic stability as well as the stability of the SMN protein [8,19,242–244]. Uba1 and SMN physically interact in the neuronal cytosol, and reduction of SMN dysregulates Uba1 splicing, perhaps leading to the reduction of Uba1 protein [232].…”

Section: Signal Transductionmentioning

confidence: 99%

Diverse role of survival motor neuron protein

Singh

Howell

Ottesen

et al. 2017

Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanism

227

194

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The multifunctional Survival Motor Neuron (SMN) protein is required for the survival of all organisms of the animal kingdom. SMN impacts various aspects of RNA metabolism through the formation and/or interaction with ribonucleoprotein (RNP) complexes. SMN regulates biogenesis of small nuclear RNPs, small nucleolar RNPs, small Cajal body-associated RNPs, signal recognition particles and telomerase. SMN also plays an important role in DNA repair, transcription, pre-mRNA splicing, histone mRNA processing, translation, selenoprotein synthesis, macromolecular trafficking, stress granule formation, cell signaling and cytoskeleton maintenance. The tissue-specific requirement of SMN is dictated by the variety and the abundance of its interacting partners. Reduced expression of SMN causes spinal muscular atrophy (SMA), a leading genetic cause of infant mortality. SMA displays a broad spectrum ranging from embryonic lethality to an adult onset. Aberrant expression and/or localization of SMN has also been associated with male infertility, inclusion body myositis, amyotrophic lateral sclerosis and osteoarthritis. This review provides a summary of various SMN functions with implications to a better understanding of SMA and other pathological conditions.

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Analysis of a membrane‐enriched proteome from postmortem human brain tissue in Alzheimer's disease

Donovan

Higginbotham

Dammer

et al. 2012

Proteomics Clinical Apps

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Purpose The present study is a discovery mode proteomics analysis of the membrane enriched fraction of post-mortem brain tissue from Alzheimer’s disease (AD) and control cases. This study aims to validate a method to identify new proteins that could be involved in the pathogenesis of AD and potentially serve as disease biomarkers. Experimental Design Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to analyze the membrane enriched fraction of human post-mortem brain tissue from five AD and five control cases of similar age. Biochemical validation of specific targets was performed by immunoblotting. Results 1709 proteins were identified from the membrane enriched fraction of frontal cortex. Label free quantification by spectral counting and G-test analysis identified 13 proteins that were significantly changed in disease. In addition to Tau (MAPT), two additional proteins found to be enriched in AD, Ubiquitin carboxy-terminal hydrolase 1 (UCHL1), and syntaxin binding protein 1 (Munc-18), were validated through immunoblotting. Discussion and clinical relevance Proteomic analysis of the membrane enriched fraction of post-mortem brain tissue identifies proteins biochemically altered in AD. Further analysis of this sub-proteome may help elucidate mechanisms behind AD pathogenesis and provide new sources of biomarkers.

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Ubiquitin carboxyl-terminal hydrolase L1 (UCHL1) regulates the level of SMN expression through ubiquitination in primary spinal muscular atrophy fibroblasts

Cited by 39 publications

References 43 publications

Dysregulation of ubiquitin homeostasis and β-catenin signaling promote spinal muscular atrophy

Dysregulation of ubiquitin homeostasis and β-catenin signaling promote spinal muscular atrophy

Diverse role of survival motor neuron protein

Analysis of a membrane‐enriched proteome from postmortem human brain tissue in Alzheimer's disease

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