The neurodegenerative diseases ALS and SMA are linked at the molecular level via the ASC-1 complex

Chi, Binkai; O’Connell, Jeremy D.; Iocolano, Alexander D; Coady, Jordan A.; Yu, Yanke; Gangopadhyay, Jaya; Gygi, Steven P.; Reed, Robin

doi:10.1093/nar/gky1093

Cited by 43 publications

(44 citation statements)

References 92 publications

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“…Finally, it will be important to understand the functional consequences of U1-mediated mRNA 3ʹ processing inhibition. For example, the expression and distribution of U1 snRNP have been demonstrated to be altered in Alzheimer Disease and other Neurodegenerative Disease [64][65][66], whether U1-mediated 3ʹ processing regulation directly contributes to these diseases remains elusive. A great challenge for this study is the dual role of U1 snRNP in splicing and PAS suppression, which makes data difficult to interpret.…”

Section: Discussionmentioning

confidence: 99%

Suboptimal RNA–RNA interaction limits U1 snRNP inhibition of canonical mRNA 3’ processing

et al. 2019

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It is increasingly appreciated that U1 snRNP transcriptomically suppresses the usage of intronic polyadenylation site (PAS) of mRNAs, an outstanding question is why frequently used PASs are not suppressed. Here we found that U1 snRNP could be transiently associated with sequences upstream of actionable PASs in human cells, and RNA-RNA interaction might contribute to the association. By focusing on individual PAS, we showed that the stable assembly of U1 snRNP near PAS might be generally required for U1 inhibition of mRNA 3ʹ processing. Therefore, actionable PASs that often lack optimal U1 snRNP docking site nearby is free from U1 inhibitory effect. Consistently, natural 5ʹ splicing site (5ʹ-SS) is moderately enriched~250 nt upstream of intronic PASs whose usage is sensitive to functional knockdown of U1 snRNA. Collectively, our results provided an insight into how U1 snRNP selectively inhibits the usage of PASs in a cellular context, and supported a prevailing model that U1 snRNP scans pre-mRNA through RNA-RNA interaction to find a stable interaction site to exercise its function in pre-mRNA processing, including repressing the usage of cryptic PASs.

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Section: Discussionmentioning

confidence: 99%

Suboptimal RNA–RNA interaction limits U1 snRNP inhibition of canonical mRNA 3’ processing

et al. 2019

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“…Indeed, EWS appears to be mislocalized in the cytoplasm of motor neurons in sporadic ALS in the absence of EWS mutations [19,124] and FUS-FTD [81]. Like for FUS and TDP43, EWS interacts with SMN and is required for its function in splicing, suggesting a role of EWS in SMA [125,126].…”

Section: Ewsmentioning

confidence: 99%

Role of RNA Binding Proteins with prion-like domains in muscle and neuromuscular diseases

Picchiarelli¹,

Dupuis²

2020

CST

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A number of neuromuscular and muscular diseases, including amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA) and several myopathies, are associated to mutations in related RNA-binding proteins (RBPs), including TDP-43, FUS, MATR3 or hnRNPA1/B2. These proteins harbor similar modular primary sequence with RNA binding motifs and low complexity domains, that enables them to phase separate and create liquid microdomains. These RBPs have been shown to critically regulate multiple events of RNA lifecycle, including transcriptional events, splicing and RNA trafficking and sequestration. Here, we review the roles of these disease-related RBPs in muscle and motor neurons, and how their dysfunction in these cell types might contribute to disease.

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“…Moreover, ASC-1 contains a conserved C-terminal ASCH domain with putative RNA-binding activity predicted in silico to coordinate pre-mRNA processing 21,22 . Interestingly, the ASC-1 complex has been recently implicated in Amyotrophic Lateral Sclerosis (ALS) pathogenesis, being proposed as a common link between ALS and SMA 23 . We demonstrated that ASC-1 plays a pivotal role in muscle, its absence leading to defects in human myotube growth 14 .…”

Section: Introductionmentioning

confidence: 99%

ASC‐1 Is a Cell Cycle Regulator Associated with Severe and Mild Forms of Myopathy

Villar-Quiles

Catervi

Cabet

et al. 2019

Annals of Neurology

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Objective Recently, the ASC-1 complex has been identified as a mechanistic link between ALS and spinal muscular atrophy (SMA), and three mutations of the ASC-1 gene TRIP4 have been associated with SMA or congenital myopathy. Our goal was to define ASC-1 neuromuscular function and the phenotypical spectrum associated with TRIP4 mutations. Methods Clinical, molecular, histological and MRI studies in 5 families with 7 novel TRIP4 mutations. FACS and Western blot in patient-derived fibroblasts and muscles and in Trip4 knocked-down C2C12 cells. Results All mutations caused ASC-1 protein depletion. The clinical phenotype was purely myopathic, ranging from lethal neonatal to mild ambulatory adult patients. It included early-onset axial and proximal weakness, scoliosis, rigid spine, dysmorphic facies, cutaneous involvement, respiratory failure and, in the older cases, dilated cardiomyopathy. Muscle biopsies showed multiminicores, nemaline rods, cytoplasmic bodies, caps, central nuclei, rimmed fibers and/or mild endomysial fibrosis. ASC-1 depletion in C2C12 and in patient-derived fibroblasts and muscles caused accelerated proliferation, altered expression of cell cycle proteins and/or shortening of the G0/G1 cell cycle phase leading to cell size reduction. Interpretation Our results expand the phenotypical and molecular spectrum of TRIP4-associated disease to include mild adult forms with or without cardiomyopathy, associate ASC-1 depletion with primary pure muscle involvement and establish TRIP4 as a causative gene for several congenital muscle diseases including nemaline, core, centronuclear or cytoplasmic-body myopathies. They also identify ASC-1 as

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The neurodegenerative diseases ALS and SMA are linked at the molecular level via the ASC-1 complex

Cited by 43 publications

References 92 publications

Suboptimal RNA–RNA interaction limits U1 snRNP inhibition of canonical mRNA 3’ processing

Suboptimal RNA–RNA interaction limits U1 snRNP inhibition of canonical mRNA 3’ processing

Role of RNA Binding Proteins with prion-like domains in muscle and neuromuscular diseases

ASC‐1 Is a Cell Cycle Regulator Associated with Severe and Mild Forms of Myopathy

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