p53-dependent c-Fos expression is a marker but not executor for motor neuron death in spinal muscular atrophy mouse models

Buettner, Jannik M.; Sowoidnich, Leonie; Gerstner, Florian; Blanco-Redondo, Beatriz; Hallermann, Stefan; Simon, Christian M.

doi:10.3389/fncel.2022.1038276

Cited by 2 publications

(2 citation statements)

References 65 publications

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“…P53 has been found to be activated in several SMA models and has been associated with the MN death that characterizes SMA 70,71,73 . To better understand any potential p53 dependent regulation in our muscle samples, we first downloaded the known transcriptional targets from the TP53 Database 74 .…”

Section: Resultsmentioning

confidence: 99%

“…Although TP53 was not differentially expressed when we compared all SMA samples to all controls, we could see an increase in TP53 in the SMAII-A, those samples which are most different from the controls (Supplemental Figure 4B). P53 has been found to be activated in several SMA models and has been associated with the MN death that characterizes SMA 70,71,73 . To better understand any potential p53 dependent regulation in our muscle samples, we first downloaded the known transcriptional targets from the TP53 Database 74 .…”

Section: P53 Target Gene Activation Is Differential Between Different...mentioning

confidence: 99%

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SMA Type II Skeletal Muscle Treated with Nusinersen shows SMN Restoration but Mitochondrial Deficiency.

Grandi,

Astord,

Gidaja

et al. 2024

Preprint

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Spinal muscular atrophy (SMA) is a rare autosomal recessive developmental disorder caused by the genetic loss or mutation of the gene SMN1 (Survival of Spinal Motor Neuron 1). SMA is classically characterized by neuromuscular symptoms, including muscular atrophy, weakness of the proximal muscles, especially those of the lower extremities, and hypotonia. Although originally thought of as a purely motor neuron disease, current research has shown that most, if not all, tissues are affected, including the muscle. Until recently, muscle problems in SMA were predominantly considered a consequence of denervation due to the motor neuron death. However, recent work using muscle specific mouse models of SMN loss, as well as skeletal stem cell specific models have shown that there are tissue specific problems in muscle due to SMN deficiency. Several years ago, SMA treatment underwent a radical transformation, with the approval of three different SMN-dependent disease modifying therapies. This includes two SMN2 splicing therapies, Risdiplam and Nusinersen, which can be administered by Type II patients that have symptom onset later in age. One main challenge for Type II SMA patients treated with Risdiplam and Nusinersen is ongoing muscle fatigue, limited mobility, and other skeletal problems, including hip dysplasia and scoliosis. To date, few molecular studies have been conducted on SMA patient derived tissues after treatment, limiting our understanding how different organ systems react to the therapies, and what additional combination therapies may be beneficial. With this goal in mind, we collected paravertebral muscle from the surgical discard in a cohort of 8 SMA Type II patients undergoing spinal surgery for scoliosis, as well as 7 non SMA controls with scoliosis and used RNA sequencing to characterize their molecular profiles. We observed that despite a restoration of the SMN mRNA and protein levels in these patients, at levels at or above the controls, a subset of patients continued to have alterations in mitochondrial metabolism and other markers of cellular stress.

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Section: Resultsmentioning

confidence: 99%

Section: P53 Target Gene Activation Is Differential Between Different...mentioning

confidence: 99%

SMA Type II Skeletal Muscle Treated with Nusinersen shows SMN Restoration but Mitochondrial Deficiency.

Grandi,

Astord,

Gidaja

et al. 2024

Preprint

View full text Add to dashboard Cite

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Pathophysiology and Management of Fatigue in Neuromuscular Diseases

Torri

Lopriore

Montano

et al. 2023

IJMS

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Fatigue is a major determinant of quality of life and motor function in patients affected by several neuromuscular diseases, each of them characterized by a peculiar physiopathology and the involvement of numerous interplaying factors. This narrative review aims to provide an overview on the pathophysiology of fatigue at a biochemical and molecular level with regard to muscular dystrophies, metabolic myopathies, and primary mitochondrial disorders with a focus on mitochondrial myopathies and spinal muscular atrophy, which, although fulfilling the definition of rare diseases, as a group represent a representative ensemble of neuromuscular disorders that the neurologist may encounter in clinical practice. The current use of clinical and instrumental tools for fatigue assessment, and their significance, is discussed. A summary of therapeutic approaches to address fatigue, encompassing pharmacological treatment and physical exercise, is also overviewed.

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p53-dependent c-Fos expression is a marker but not executor for motor neuron death in spinal muscular atrophy mouse models

Cited by 2 publications

References 65 publications

SMA Type II Skeletal Muscle Treated with Nusinersen shows SMN Restoration but Mitochondrial Deficiency.

SMA Type II Skeletal Muscle Treated with Nusinersen shows SMN Restoration but Mitochondrial Deficiency.

Pathophysiology and Management of Fatigue in Neuromuscular Diseases

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