Aug 2026· Frontiers in Molecular Biosciences· Vol 13· 0 citations· 326 references
TL;DR
How dysfunction in NMD pathway components—specifically core degradation factors, the exon junction complex, and neuron-specific splicing regulators—underpins an extensive array of neurodevelopmental disorders (NDDs) is examined.
Abstract
Nonsense-mediated mRNA decay (NMD) is a basic post-transcriptional mechanism ensuring the fidelity of many biological processes including brain development. Together with alternative splicing, it regulates the inclusion of poison exons. NMD is involved in the control of multiple processes during brain development such as neural progenitor proliferation and differentiation, neuronal migration, axonal guidance, and synaptic plasticity. Under physiological conditions, this mechanism safeguards neuronal identity and the functional maturation of the brain. When disrupted, the consequences range from structural cerebral anomalies to cognitive impairment and epilepsy. This review examines NMD-mediated regulatory mechanisms across different stages of brain development. Special emphasis is placed on how dysfunction in NMD pathway components—specifically core degradation factors, the exon junction complex, and neuron-specific splicing regulators—underpins an extensive array of neurodevelopmental disorders (NDDs). Furthermore, we delineate the relationship between the position of a premature termination codon (PTC) within a transcript and the resulting molecular outcome. While the degradation of aberrant mRNAs often leads to haploinsufficiency, their escape from NMD might result in the accumulation of truncated proteins with dominant-negative effects, thereby causing specific clinical phenotypes in affected patients. Elucidating these mechanisms is essential for both the interpretation of variant pathogenicity and the development of targeted therapeutic strategies.
Current evidence on the RNA regulatory networks in PD is examined, highlighting the role of transcript isoforms and RBPs in neuronal dysfunction and emerging data suggest that dysregulation of RNA binding proteins (RBPs) may influence RNA processing in PD.
Maria Giusy Bruno, G. Menichetti, Angela Valentino et al.· Genes· 0 citations
Haploinsufficiency in SYNGAP1 causes a severe neurodevelopmental syndrome. SYNGAP1 protein is mainly detected in neuronal synapses. However, SYNGAP1 RNA is more widely expressed and strongly regulated via alternative splicing: alternative 3’ splice site (A3SS) inclusion leads to non-productive transcripts that are degraded through nonsense-mediated decay. Recently, splice-switching oligonucleotides (SSOs) that redirect SYNGAP1 splicing to increase SYNGAP1 protein levels were developed. However, we hypothesized that during neuronal maturation, non-productive splicing may decrease to enhance functional transcripts in mature neurons. This would reduce the abundance of the SSO target transcript, limiting the potential for SSO treatment to increase neuronal SYNGAP1 expression. Using neural differentiation of human induced pluripotent stem cells, we show that the A3SS transcript is abundant in neural progenitors, astrocytes, microglia and immature neurons, with minimal presence in mature neurons. These data imply that SSOs targeting A3SS might lack therapeutic efficacy to rescue the neuronal phenotypes associated with SYNGAP1 haploinsufficiency. Graphical abstract
J. A. Kamp, K. N. Wijnant, N. Maas et al.· bioRxiv· 0 citations
Proper nervous system development is critical for brain function, and deficits in neural development are implicated in many brain disorders. Neurons are distinctly polarized cells where mRNA can be transported to distal structures like axons and dendrites. Recent discoveries of widespread mRNA chemical modifications raise the question of their post-transcriptional regulatory role in brain development and function. N6-methyladenosine (m6A), installed by the METTL3/METTL14 methyltransferase complex, is the most prevalent internal mRNA modification, influencing stability, translation, splicing, and localization. However, the impact of m6A modification on RNA transport in developing neurons is not well understood. In this study, we find that the ablation of Mettl14 in postmitotic neurons leads to impaired axonal projection during corticogenesis. RNA-seq and single-molecule in situ hybridization reveal mislocalization of mRNAs in neurites of neurons with m6A loss-of-function. Furthermore, m6A-SAC-seq to identify a single nucleotide resolution m6A maps in the perinatal brain uncovers m6A-tagged transcripts associated with synapse organization, mRNA processing, and axonogenesis. We also identify YTHDF2 as the reader protein responsible for mRNA transport in callosal projection axons. YTHDF2 interacts with motor proteins, translational regulators, and microtubules to facilitate distal transport of m6A-tagged mRNA. Our data suggest that FMRP may serve as a context-guiding interactor that reshapes the YTHDF2 complex by recruiting specific cofactors and motor proteins, thereby promoting transport rather than degradation of m⁶A-tagged transcripts. Together, these findings provide insight into the epitranscriptomic mechanisms governing axon projection and guidance during mammalian cortical neurogenesis. Precise mRNA transport into neurites is essential for neural circuit formation. Here, the authors show that m6A RNA marks recruit YTHDF2-associated transport machinery that favors transport over degradation, localizing selected mRNAs to neurites to promote cortical axon projection.
Bonsang Koo, Ajeet Kumar, H. Hwang et al.· Nature Communications· 0 citations
A homozygous synonymous NPR2 variant is identified in an individual with AMDM and aberrant splicing induced by a synonymous variant as a disease-causing mechanism affecting a core developmental signaling pathway is established.
N. B. Acikgoz, Hasan Basri Kılıç, Gizem Urel Demir et al.· Differentiation; research in...· 0 citations
It is shown that PTC location critically determines not only NMD efficiency and its variability across cells, but also the spectrum of resulting protein products, including truncated proteins arising from premature termination, full-length proteins generated through translational readthrough, and N-terminally truncated isoforms produced by downstream reinitiation.
The adenosine deaminases acting on RNA (ADAR) family of enzymes (ADAR1 and ADAR2) catalyze adenosine-to-inosine (A-to-I) RNA editing. This post-transcriptional change is remarkably prevalent in the central nervous system (CNS). ADAR-mediated editing is critical for proper brain development, synaptic plasticity, and immunological homeostasis in the central nervous system (CNS) via recoding neurotransmitter receptors and ion channels. Conversely, a wide range of CNS disorders, such as neurodegenerative diseases (Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis), neuropsychiatric conditions (schizophrenia, bipolar disorder, and major depression), cerebrovascular diseases, and gliomas, are now linked to dysregulation of ADAR activity, whether through loss-of-function mutations, altered expression, or mislocalization. To address the main question of whether altered RNA editing is a fundamental driver of pathogenesis, a compensatory response, or a context-dependent modulator, this review critically synthesizes existing evidence. The basic processes of ADAR enzymes and their regulation throughout neurodevelopment are first described. Next, we thoroughly assess the unique molecular fingerprints of ADAR dysregulation across several CNS disorders, emphasizing recurring themes such as Alu RNA hypo-editing, induction of innate immunity, and GRIA2 editing, which can cause excitotoxicity. Lastly, we examine new treatment approaches that use or reinstate ADAR activity, such as small-molecule modulators and site-directed RNA editing tools (leveraging endogenous ADAR for programmable editing of RNA [LEAPER], clustered ADAR-recruiting guide RNAs (gRNAs) for effective RNA editing [CLUSTER], and mimicking inverted repeats to recruit ADARs using engineered oligoribonucleotides [MIRROR]). We summarize by reviewing key obstacles to clinical translation, including crossing the blood–brain barrier, the risks of off-target editing, and the challenges of achieving spatiotemporal accuracy. We also list important open topics for further investigation.
