RNA methylation influences TDP43 binding and disease pathogenesis in models of amyotrophic lateral sclerosis and frontotemporal dementia

McMillan, Michael; Gómez, Nicolás; Hsieh, Caroline; Bekier, Michael E.; Li, Xingli; Miguez, Roberto; Tank, Elizabeth M.H.; Barmada, Sami J.

doi:10.1016/j.molcel.2022.12.019

Cited by 50 publications

(34 citation statements)

References 102 publications

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“…Moreover, these results indirectly suggest that RNA modifications like m 6 A, which are involved in determining structure and interaction with proteins (65), could potentially play a role in the pathological process leading to neurodegeneration by influencing RNA aggregation dynamics. This could be an intriguing field to explore, since recent evidence reports that m 6 A methylated RNAs are more abundant in spinal cords of patients affected by ALS (66).…”

Section: Discussionmentioning

confidence: 99%

ALS-associated FUS mutation reshapes the RNA and protein composition of Stress Granules

Mariani,

Setti,

Castagnetti

et al. 2023

Preprint

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Stress Granules (SG) formation is a cellular protection mechanism in harmful conditions, constituting a storage for untranslated mRNAs and RNA-binding proteins (RBPs); however, these condensates can turn into pathological aggregates, that in neurons are related to the onset of neurodegenerative diseases, like Amyotrophic Lateral Sclerosis (ALS). Mutations in the RBP FUS leading to its cytoplasmic mis-localization are causatively linked to ALS, since they mediate its accumulation in SGs, triggering their transition towards cytotoxic inclusions. Here, we describe the SG transcriptome in a neural context and compare with datasets from other systems, identifying both common rules and diversifying characteristics for SG recruitment of transcripts. We demonstrate that SG dynamics and RNA content are strongly modified by the incorporation of aberrantly localized mutant FUS, switching to a more unstructured, AU-rich SG transcriptome and losing a wide population of GC-rich, structured RNAs. We show that these alterations mainly depend on mutant FUS which favors the SG incorporation of its protein interactors and in turn of their target RNAs. Our data give a comprehensive view of the molecular differences between physiological and pathological SG in ALS conditions, showing how a single mutation is sufficient to impact the RNA and protein population of these condensates.

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Section: Discussionmentioning

confidence: 99%

ALS-associated FUS mutation reshapes the RNA and protein composition of Stress Granules

Mariani,

Setti,

Castagnetti

et al. 2023

Preprint

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“…Notably, increased global m6A levels are associated with shorter half-life of m6A-tagged transcripts 49 , while pervasive destabilization of RNA has been observed in ALS broblasts and iPSCs overexpressing TDP43 50 , suggesting that dysregulated m6A modi cation may be involved in ALS pathophysiology. This is further supported by the observation that TDP43 preferentially binds to m6Amodi ed RNA and mediates neurotoxicity in association with the m6A reader YTHDF2 51 . Herein, we presented evidence supporting the association between m6A RNA modi cation and ALS pathogenesis by focusing on the pathogenic role played by RBMX.…”

Section: Discussionmentioning

confidence: 64%

N6-methyladenosine reader RBMX is essential for motor cortex excitatory neuron survival in amyotrophic lateral sclerosis

Liu

Liiu

et al. 2023

Preprint

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Despite being one of the most common RNA modifications, the role of N6-methyladenosine (m6A) in amyotrophic lateral sclerosis (ALS) remains incompletely understood. The present study aims to explore the involvement of RBMX-mediated m6A posttranscriptional regulation in ALS pathophysiology. We examined the cellular effects of downregulating Rbmx in murine motor neuron cell line NSC-34, and the transcriptomic changes in human cell line HEK293T. The single cell sequencing dataset generated from primary motor cortex of ALS and control subjects was further analyzed, with the expression of RBMX-regulated genes compared between patients and controls across different cell types. Finally, the genetic variation landscape of m6A genes were inspected in a whole-exome sequencing (WES) cohort involving 508 ALS patients. We demonstrated that the disturbance of RBMX expression can induce transcriptomic changes selectively affecting excitatory motoneuron survival. The machine learning models identified several RBMX-regulated hub genes including TBKBP1. In addition, we found that the RBMX mutants affected the disease onset age and survival of ALS patients in a sex-dependent manner. Taken together, our integrated analyses highlighted the emerging roles played by RBMX affecting excitatory motor neuron viability in ALS, which may have important implications in understanding ALS pathogenesis.

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“…Therefore, further studies on the relationship of METTL3 with developing brain disorders are warranted. Furthermore, although a study has reported the downregulation of METTL3 in amyotrophic lateral sclerosis (ALS), which is a progressive neurodegenerative disease resulting in the death of upper and lower motor neurons, its underlying mechanisms have not been clarified yet and needs further clarification [ 75 ].…”

Section: Discussionmentioning

confidence: 99%

The Regulatory Network of METTL3 in the Nervous System: Diagnostic Biomarkers and Therapeutic Targets

2023

Biomolecules

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Methyltransferase-like 3 (METTL3) is a typical component of N6-methyladenosine writers that exhibits methyltransferase activity and deposits methyl groups on RNA. Currently, accumulating studies have demonstrated the involvement of METTL3 in the regulation of neuro-physiological and pathological events. However, no reviews have comprehensively summarized and analyzed the roles and mechanisms of METTL3 in these events. Herein, we are focused on reviewing the roles of METTL3 in regulating normal neurophysiological (Neurogenesis, Synaptic Plasticity and Glial Plasticity, Neurodevelopment, Learning and Memory,) and neuropathological (Autism Spectrum Disorder, Major Depressive Disorder, Neurodegenerative disorders, Brain Tumors, Brain Injuries, and Other Brain Disorders) events. Our review found that although the down-regulated levels of METTL3 function through different roles and mechanisms in the nervous system, it primarily inactivates neuro-physiological events and triggers or worsens neuropathological events. In addition, our review suggests that METTL3 could be used as a diagnostic biomarker and therapeutic target in the nervous system. Collectively, our review has provided an up-to-date research outline of METTL3 in the nervous system. In addition, the regulatory network for METTL3 in the nervous system has been mapped, which could provide directions for future research, biomarkers for clinical diagnosis, and targets for disease treatment. Furthermore, this review has provided a comprehensive view, which could improve our understanding of METTL3 functions in the nervous system.

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RNA methylation influences TDP43 binding and disease pathogenesis in models of amyotrophic lateral sclerosis and frontotemporal dementia

Cited by 50 publications

References 102 publications

ALS-associated FUS mutation reshapes the RNA and protein composition of Stress Granules

ALS-associated FUS mutation reshapes the RNA and protein composition of Stress Granules

N6-methyladenosine reader RBMX is essential for motor cortex excitatory neuron survival in amyotrophic lateral sclerosis

The Regulatory Network of METTL3 in the Nervous System: Diagnostic Biomarkers and Therapeutic Targets

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