Converging Mechanisms of p53 Activation Drive Motor Neuron Degeneration in Spinal Muscular Atrophy

Simon, Christian M.; Dai, Ya; Alstyne, Meaghan Van; Koutsioumpa, Charalampia; Pagiazitis, John G.; Chalif, Joshua I.; Wang, Xiaojian; Rabinowitz, Joseph E.; Henderson, Christopher E.; Pellizzoni, Livio; Mentis, George Z.

doi:10.1016/j.celrep.2017.12.003

Cited by 85 publications

(216 citation statements)

References 70 publications

(103 reference statements)

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“…This finding does not preclude the possibility that other molecules downstream of AKT were stimulated by physical activity in Smn 2B/− animals. Examining the effect of exercise on alternative targets of AKT such as p53, for example (Gottlieb et al 2002), is worth pursuing particularly since inhibition of p53 has been shown to prevent cell death in SMA (Simon et al 2017). Consistent with previous work (Biondi et al 2008(Biondi et al , 2015, we found that ERK-ELK1 signalling was elevated in the muscles of SMA-like mice compared to their healthy counterparts.…”

Section: Discussionsupporting

confidence: 89%

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Mechanisms of exercise‐induced survival motor neuron expression in the skeletal muscle of spinal muscular atrophy‐like mice

Mikhail

Ljubicic

2019

The Journal of Physiology

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Key points Spinal muscular atrophy (SMA) is a health‐ and life‐limiting neuromuscular disorder caused by a deficiency in survival motor neuron (SMN) protein. While historically considered a motor neuron disease, current understanding of SMA emphasizes its systemic nature, which requires addressing affected peripheral tissues such as skeletal muscle in particular. Chronic physical activity is beneficial for SMA patients, but the cellular and molecular mechanisms of exercise biology are largely undefined in SMA. After a single bout of exercise, canonical responses such as skeletal muscle AMP‐activated protein kinase (AMPK), p38 mitogen‐activated protein kinase (p38) and peroxisome proliferator‐activated receptor γ coactivator 1α (PGC‐1α) activation were preserved in SMA‐like Smn2B/− animals. Furthermore, molecules involved in SMN transcription were also altered following physical activity. Collectively, these changes were coincident with an increase in full‐length SMN transcription and corrective SMN pre‐mRNA splicing. This study advances understanding of the exercise biology of SMA and highlights the AMPK–p38–PGC‐1α axis as a potential regulator of SMN expression in muscle. Abstract Chronic physical activity is safe and effective in spinal muscular atrophy (SMA) patients, but the underlying cellular events that drive physiological adaptations are undefined. We examined the effects of a single bout of exercise on molecular mechanisms associated with adaptive remodelling in the skeletal muscle of Smn2B/− SMA‐like mice. Skeletal muscles were collected from healthy Smn2B/+ mice and Smn2B/− littermates at pre‐ (postnatal day (P) 9), early‐ (P13) and late‐ (P21) symptomatic stages to characterize SMA disease progression. Muscles were also collected from Smn2B/− animals exercised to fatigue on a motorized treadmill. Intracellular signalling and gene expression were examined using western blotting, confocal immunofluorescence microscopy, real‐time quantitative PCR and endpoint PCR assays. Basal skeletal muscle AMP‐activated protein kinase (AMPK) and p38 mitogen‐activated protein kinase (p38) expression and activity were not affected by SMA‐like conditions. Canonical exercise responses such as AMPK, p38 and peroxisome proliferator‐activated receptor γ coactivator‐1α (PGC‐1α) activation were observed following a bout of exercise in Smn2B/− animals. Furthermore, molecules involved in survival motor neuron (SMN) transcription, including protein kinase B (AKT) and extracellular signal‐regulated kinases (ERK)/ETS‐like gene 1 (ELK1), were altered following physical activity. Acute exercise was also able to mitigate aberrant proteolytic signalling in the skeletal muscle of Smn2B/− mice. Collectively, these changes were coincident with an exercise‐evoked increase in full‐length SMN mRNA expression. This study advances our understanding of the exercise biology of SMA and highlights the AMPK–p38–PGC‐1α axis as a potential regulator of SMN expression alongside AKT and ERK/ELK1 signalling.

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Section: Discussionsupporting

confidence: 89%

“…), is worth pursuing particularly since inhibition of p53 has been shown to prevent cell death in SMA (Simon et al . ). Consistent with previous work (Biondi et al .…”

Section: Discussionmentioning

confidence: 97%

Mechanisms of exercise‐induced survival motor neuron expression in the skeletal muscle of spinal muscular atrophy‐like mice

Mikhail

Ljubicic

2019

The Journal of Physiology

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“…We sought to investigate the effects of increased expression of human Stasimon (abbreviated as STAS) on the phenotype of SMNΔ7 SMA mice by intracerebroventricular (ICV) injection of self-complementary AAV9 vectors at P0, an established method to study SMA disease mechanisms in vivo (Passini et al, 2010;Simon et al, 2017;Van Alstyne et al, 2018a). RT-qPCR analysis confirmed that injection of AAV9-STAS as well as AAV9-GFP and AAV9-SMN, which were used as negative and positive controls, respectively, resulted in robust expression of the corresponding mRNAs in the spinal cord of SMA mice at P11 ( Figure 1A).…”

Section: Aav9-mediated Stasimon Gene Delivery Improves Motor Functionmentioning

confidence: 99%

“…To examine the selectivity of Stasimon's effects on synaptic loss, we investigated neuromuscular junction (NMJ) innervation of the quadratus lumborum (QL), a disease-relevant axial muscle innervated by vulnerable L1-L3 motor neurons that is severely denervated in SMA mice (Fletcher et al, 2017;Simon et al, 2017;Van Alstyne et al, 2018a). To do so, we used antibodies against neurofilament (NF-M) and synaptophysin (SYP) as presynaptic markers and fluorescently-labeled α-bungarotoxin (BTX) to label the acetylcholine receptor clusters on muscle fibers.…”

Section: Aav9-stas Rescues the Loss Of Proprioceptive Synapses On Smamentioning

confidence: 99%

Stasimon contributes to the loss of sensory synapses and motor neuron death in a mouse model of spinal muscular atrophy

Simon

Alstyne

Lotti

et al. 2019

Preprint

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Reduced expression of the SMN protein causes spinal muscular atrophy (SMA) -an inherited neurodegenerative disease characterized by multiple synaptic deficits and motor neuron loss. Here, we show that AAV9-mediated delivery of Stasimon -a gene encoding an ER-resident transmembrane protein regulated by SMN -improves motor function in a mouse model of SMA through multiple mechanisms. In proprioceptive neurons of SMA mice, Stasimon overexpression prevents the loss of afferent synapses on motor neurons and enhances sensory-motor neurotransmission. In SMA motor neurons, Stasimon suppresses the neurodegenerative process by selectively reducing phosphorylation but not upregulation of the tumor suppressor p53, both of which are converging events required to trigger neuronal death. We further show that Stasimon deficiency synergizes with SMA-related mechanisms of p53 upregulation to induce phosphorylation of p53. These findings identify Stasimon dysfunction induced by SMN deficiency as an upstream driver of cellular pathways that lead to synaptic loss and motor neuron degeneration, revealing a dual contribution of Stasimon to motor circuit pathology in SMA.

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“…SMA is characterized by loss of lower motor neurons, leading to muscle atrophy and wasting. However, the molecular mechanisms leading to motor neuron death in SMA remain complex and unresolved (22)(23)(24)(25)(26). Although classically known to play a role in the biogenesis of ribonucleoparticles (RNPs) (27), SMN protein is a strong candidate to be directly implicated in the control of translation.…”

Section: Introductionmentioning

confidence: 99%

SMN-primed ribosomes modulate the translation of transcripts related to Spinal Muscular Atrophy

Lauria

Bernabò

Tebaldi

et al. 2019

Preprint

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The contribution of ribosome heterogeneity and ribosome-associated factors to the molecular control of proteomes in health and disease remains enigmatic. We demonstrate that Survival Motor Neuron (SMN) protein, loss of which causes the neuromuscular disease spinal muscular atrophy (SMA), binds to ribosomes and that this interaction is tissuedependent. SMN-primed ribosomes are positioned within the first five codons of a set of mRNAs which are enriched in IRES-like sequences in the 5'UTR and rare codons at the beginning of their coding sequence. Loss of SMN at early-stages of SMA induces translational defects in vivo, characterized by ribosome depletion in rare codons at the third and fifth position of the coding sequence. These positional defects cause ribosome depletion from mRNAs bound by SMN-primed ribosomes and translational impairment of proteins involved in motor neuron function and stability, including acetylcholinesterase. Thus, SMN plays a crucial role in the regulation of ribosome fluxes along mRNAs which encode proteins relevant to SMA pathogenesis.

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Converging Mechanisms of p53 Activation Drive Motor Neuron Degeneration in Spinal Muscular Atrophy

Cited by 85 publications

References 70 publications

Mechanisms of exercise‐induced survival motor neuron expression in the skeletal muscle of spinal muscular atrophy‐like mice

Mechanisms of exercise‐induced survival motor neuron expression in the skeletal muscle of spinal muscular atrophy‐like mice

Stasimon contributes to the loss of sensory synapses and motor neuron death in a mouse model of spinal muscular atrophy

SMN-primed ribosomes modulate the translation of transcripts related to Spinal Muscular Atrophy

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