Severe SMA mice show organ impairment that cannot be rescued by therapy with the HDACi JNJ-26481585

Schreml, Julia; Rießland, Markus; Paterno, Mario; Garbes, Lutz; Roßbach, Kristina; Ackermann, Bastian; Kramer, Jan S.; Somers, Eilidh; Parson, Simon H.; Heller, Raoul; Berkessel, Albrecht; Sterner-Kock, Anja; Wirth, Brunhilde

doi:10.1038/ejhg.2012.222

Cited by 60 publications

(50 citation statements)

References 69 publications

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“…Examination of quercetin-treated mice postmortem revealed the presence of widespread gross organ defects previously reported in SMA mice (Figure 7J), where systemic pathology is known to target organs including the heart and liver (10,14,16). In order to examine the possible causes of this failure to ameliorate nonneuromuscular, systemic pathology (even when quercetin was administered systemically via i.p.…”

Section: Figurementioning

confidence: 88%

“…However, recent studies have revealed that SMA, particularly in its most severe forms, is a multisystem disorder (10), with other regions of the nervous system also being affected (e.g., the hippocampus; ref. 11) as well as nonneuronal tissues and organs, including heart (12), vasculature (13), liver (14), pancreas (15), lung, and intestines (16). This suggests that SMN deficiency causes perturbations across a wide range of cells and tissues in SMA, albeit with motor neurons being the most vulnerable cell type.…”

Section: Introductionmentioning

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.

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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: Figurementioning

confidence: 88%

Section: Introductionmentioning

confidence: 99%

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

Wishart¹,

Mutsaers²,

Rießland³

et al. 2014

J. Clin. Invest.

Self Cite

165

253

View full text Add to dashboard Cite

show abstract

“…Neuromuscular defects are the most obvious hallmarks of SMA, but SMN is ubiquitously expressed and numerous studies have suggested nonneuronal requirements for SMN function in heart (57-59), liver (60), muscle vascular system (61), lung, intestine (62), and pancreatic islets (63). Therefore, it was not surprising that endosomal defects were observed in other C. elegans tissues when SMN levels were compromised.…”

Section: Discussionmentioning

confidence: 99%

Decreased function of survival motor neuron protein impairs endocytic pathways

Dimitriadi

Derdowski

Kalloo

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Spinal muscular atrophy (SMA) is caused by depletion of the ubiquitously expressed survival motor neuron (SMN) protein, with 1 in 40 Caucasians being heterozygous for a disease allele. SMN is critical for the assembly of numerous ribonucleoprotein complexes, yet it is still unclear how reduced SMN levels affect motor neuron function. Here, we examined the impact of SMN depletion in Caenorhabditis elegans and found that decreased function of the SMN ortholog SMN-1 perturbed endocytic pathways at motor neuron synapses and in other tissues. Diminished SMN-1 levels caused defects in C. elegans neuromuscular function, and smn-1 genetic interactions were consistent with an endocytic defect. Changes were observed in synaptic endocytic proteins when SMN-1 levels decreased. At the ultrastructural level, defects were observed in endosomal compartments, including significantly fewer docked synaptic vesicles. Finally, endocytosis-dependent infection by JC polyomavirus (JCPyV) was reduced in human cells with decreased SMN levels. Collectively, these results demonstrate for the first time, to our knowledge, that SMN depletion causes defects in endosomal trafficking that impair synaptic function, even in the absence of motor neuron cell death.endocytic trafficking | survival motor neuron | spinal muscular atrophy | C. elegans | infection S pinal muscular atrophy (SMA) is one of the most severe neuromuscular diseases of childhood, with an incidence of 1 in 10,000 live births and a high carrier frequency of roughly 1 in 40 Caucasians (1-3). SMA is caused by reduced levels of the ubiquitously expressed survival of motor neuron (SMN) protein and results in degeneration of α-spinal cord motor neurons, muscle weakness, and/or death. Two human genes encode the SMN protein, SMN1 and SMN2. SMA alleles arise at relatively high frequency due to small intrachromosomal de novo rearrangements including the SMN1 locus (4). Patients often carry homozygous SMN1 deletions, although missense and nonsense alleles exist (5). Multiple copies of SMN2 rarely compensate for loss of SMN1 due to a C > T nucleotide change in SMN2 exon 7 that perturbs pre-mRNA splicing and results in a truncated protein of diminished function and stability (SMNΔ7) (5-9).SMN has numerous roles and interacts with various proteins, yet it remains unclear which interactions are most pertinent to SMA pathogenesis. As a component of the Gemin complex, SMN is required for biogenesis of small nuclear ribonucleoprotein (snRNP) particles critical for pre-mRNA splicing (10-12). Furthermore, SMN is needed for stress granule formation (13,14), is found in RNP granules moving through neuronal processes, and is part of RNP complexes implicated in synaptic local translation (15)(16)(17)(18)(19)(20). Additional roles for SMN, in transcription (21), in the PTEN-mediated protein synthesis pathway (22), in translational control (23), and in cell proliferation/differentiation (24), have been described. Importantly, no consensus has been reached regarding the cellular and molecular pathways wh...

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“…It is important to note that SMA is a complex and multisystemic disorder, although it is phenotypically expressed mainly as a neuromuscular disease [13,61,106,107]. It appears that muscle and nerve may be independently affected by SMN deficiency [17,107], and muscle has only a minor impact on SMA pathogenesis.…”

Section: Discussionmentioning

confidence: 99%

Chronic Treatment with the AMPK Agonist AICAR Prevents Skeletal Muscle Pathology but Fails to Improve Clinical Outcome in a Mouse Model of Severe Spinal Muscular Atrophy

et al. 2016

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Spinal muscular atrophy (SMA) is a genetic neuromuscular disorder characterized by spinal and brainstem motor neuron (MN) loss and skeletal muscle paralysis. Currently, there is no effective treatment other than supportive care to ameliorate the quality of life of patients with SMA. Some studies have reported that physical exercise, by improving muscle strength and motor function, is potentially beneficial in SMA. The adenosine monophosphate-activated protein kinase agonist 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR) has been reported to be an exercise mimetic agent that is able to regulate muscle metabolism and increase endurance both at rest and during exercise. Chronic AICAR administration has been shown to ameliorate the dystrophic muscle phenotype and motor behavior in the mdx mouse, a model of Duchenne muscular dystrophy. Here, we investigated whether chronic AICAR treatment was able to elicit beneficial effects on motor abilities and neuromuscular histopathology in a mouse model of severe SMA (the SMNΔ7 mouse). We report that AICAR improved skeletal muscle atrophy and structural changes found in neuromuscular junctions of SMNΔ7 animals. However, although AICAR prevented the loss of glutamatergic excitatory synapses on MNs, this compound was not able to mitigate MN loss or the microglial and astroglial reaction occurring in the spinal cord of diseased mice. Moreover, no improvement in survival or motor performance was seen in SMNΔ7 animals treated with AICAR. The beneficial effects of AICAR in SMA found in our study are SMN-independent, as no changes in the expression of this protein were seen in the spinal cord and skeletal muscle of diseased animals treated with this compound.

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Severe SMA mice show organ impairment that cannot be rescued by therapy with the HDACi JNJ-26481585

Cited by 60 publications

References 69 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

Decreased function of survival motor neuron protein impairs endocytic pathways

Chronic Treatment with the AMPK Agonist AICAR Prevents Skeletal Muscle Pathology but Fails to Improve Clinical Outcome in a Mouse Model of Severe Spinal Muscular Atrophy

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