Loss‐of‐function variants in RNA binding motif protein X‐linked induce neuronal defects contributing to amyotrophic lateral sclerosis pathogenesis

• Published in: MedComm (2020) 2024-09, Vol.5 (9), p.e712-n/a
• Main Authors: He, Di, He, Xinyi, Shen, Dongchao, Liu, Liyang, Yang, Xunzhe, Hao, Meng, Wang, Yi, Li, Yi, Liu, Qing, Liu, Mingsheng, Wang, Jiucun, Zhang, Xue, Cui, Liying
• Format: Article
• Language: English
• Subjects: ALS; Amyotrophic lateral sclerosis; m6A modification; Original; Pathogenesis; RBMX; single‐cell sequencing; whole‐exome sequencing
• ISSN: 2688-2663; 2688-2663
• DOI: 10.1002/mco2.712

Despite being one of the most prevalent RNA modifications, the role of N6‐methyladenosine (m6A) in amyotrophic lateral sclerosis (ALS) remains ambiguous. In this investigation, we explore the contribution of genetic defects of m6A‐related genes to ALS pathogenesis. We scrutinized the mutation landscape of m6A genes through a comprehensive analysis of whole‐exome sequencing cohorts, encompassing 508 ALS patients and 1660 population‐matched controls. Our findings reveal a noteworthy enrichment of RNA binding motif protein X‐linked (RBMX) variants among ALS patients, with a significant correlation between pathogenic m6A variants and adverse clinical outcomes. Furthermore, Rbmx knockdown in NSC‐34 cells overexpressing mutant TDP43Q331K results in cell death mediated by an augmented p53 response. Similarly, RBMX knockdown in ALS motor neurons derived from induced pluripotent stem cells (iPSCs) manifests morphological defects and activation of the p53 pathway. Transcriptional analysis using publicly available single‐cell sequencing data from the primary motor cortex indicates that RBMX‐regulated genes selectively influence excitatory neurons and exhibit enrichment in ALS‐implicated pathways. Through integrated analyses, our study underscores the emerging roles played by RBMX in ALS, suggesting a potential nexus between the disease and dysregulated m6A‐mediated mRNA metabolism. The dysregulation of m6A modification has gained recognition as a crucial factor in the development of amyotrophic lateral sclerosis (ALS). Among the m6A reader proteins, RNA binding motif protein X‐linked (RBMX) stands out with a notable enrichment of variants in ALS patients, and the presence of pathogenic RBMX variants is associated with a faster disease progression. In vitro experiments have provided evidence that reducing RBMX levels can result in neuronal defects. Additionally, bioinformatic analyses have supported these findings by revealing that RBMX‐associated genes specifically impact excitatory neurons. Furthermore, these genes are involved in the regulation of pathways and genes associated with neurodegeneration and RNA metabolism, underscoring the relevance of RBMX in ALS pathogenesis.