Nucleolar Reorganization After Cellular Stress is Orchestrated by SMN Shuttling between Nuclear Compartments

Musawi, Shaqraa; Donnio, Lise-Marie; Magnani, Charlène; Binda, Olivier; Côté, Jocelyn; Lomonte, Patrick; Mari, Pierre-Olivier; Giglia-Mari, Giuseppina

doi:10.1101/2022.11.04.515196

Cited by 2 publications

(2 citation statements)

References 49 publications

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“…In total, our AP-MS data identified Srp-19, -54, -68 and -72, suggesting that this putative function of the SMN complex is conserved in metazoa. Other connections to the nucleolus are evident; SMN and other Cajal body components are known to relocalize to the nucleolus during genotoxic stress [77,78]. In support of these findings, we identified the large subunit of RNA pol I (Rpa1), topoisomerase 2 (Top2) and fibrillarin (Fib) in our dataset (Fig.…”

Section: Cellular Components Identified By Purification Of the Drosop...supporting

confidence: 80%

Chaperoning the chaperones: Proteomic analysis of the SMN complex reveals conserved and etiologic connections to the proteostasis network

Matera,

Steiner,

Mills

et al. 2024

Preprint

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Molecular chaperones and co-chaperones are highly conserved cellular components that perform variety of duties related to the proper three-dimensional folding of the proteome. The web of factors that carries out this essential task is called the proteostasis network (PN). Ribonucleoproteins (RNPs) represent an underexplored area in terms of the connections they make with the PN. The Survival Motor Neuron (SMN) complex is an RNP assembly chaperone and serves as a paradigm for studying how specific small nuclear (sn)RNAs are identified and paired with their client substrate proteins. SMN protein is the eponymous component of a large complex required for the biogenesis of uridine-rich small nuclear ribonucleoproteins (U-snRNPs) and localizes to distinct membraneless organelles in both the nucleus and cytoplasm of animal cells. SMN forms the oligomeric core of this complex, and missense mutations in its YG box self-interaction domain are known to cause Spinal Muscular Atrophy (SMA). The basic framework for understanding how snRNAs are assembled into U-snRNPs is known, the pathways and mechanisms used by cells to regulate their biogenesis are poorly understood. Given the importance of these processes to normal development as well as neurodegenerative disease, we set out to identify and characterize novel SMN binding partners. Here, we carried out affinity purification mass spectrometry (AP-MS) of SMN using stable fly lines exclusively expressing either wildtype or SMA-causing missense alleles. Bioinformatic analyses of the pulldown data, along with comparisons to proximity labeling studies carried out in human cells, revealed conserved connections to at least two other major chaperone systems including heat shock folding chaperones (HSPs) and histone/nucleosome assembly chaperones. Notably, we found that heat shock cognate protein Hsc70-4 and other HspA family members preferentially interacted with SMA-causing alleles of SMN. Hsc70-4 is particularly interesting because its mRNA is aberrantly sequestered by a mutant form of TDP-43 in mouse and Drosophila ALS (Amyotrophic Lateral Sclerosis) disease models. Most important, a missense allele of Hsc70-4 (HspA8 in mammals) was recently identified as a bypass suppressor of the SMA phenotype in mice. Collectively, these findings suggest that chaperone-related dysfunction lies at the etiological root of both ALS and SMA.

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Section: Cellular Components Identified By Purification Of the Drosop...supporting

confidence: 80%

Chaperoning the chaperones: Proteomic analysis of the SMN complex reveals conserved and etiologic connections to the proteostasis network

Matera,

Steiner,

Mills

et al. 2024

Preprint

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“…DNA damage response and cellular stress are also major hallmarks of SMA pathology [70][71][72] . Thus, we sought to investigate if SMN-targeted therapies could ameliorate these features.…”

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

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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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Nucleolar Reorganization After Cellular Stress is Orchestrated by SMN Shuttling between Nuclear Compartments

Cited by 2 publications

References 49 publications

Chaperoning the chaperones: Proteomic analysis of the SMN complex reveals conserved and etiologic connections to the proteostasis network

Chaperoning the chaperones: Proteomic analysis of the SMN complex reveals conserved and etiologic connections to the proteostasis network

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

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