Dynamic m⁶A Methylation in Neurodevelopmental and Neurodegenerative Disorders.
5 affiliations
- 1College of Osteopathic Medicine, Kansas City University, Farber-McIntire Campus, 2901 St. Johns Blvd, Joplin, MO 64804-1598, USA.
- 2The Human Physiology Program, Sargent College of Health & Rehabilitation Sciences, Boston University, 635 Commonwealth Avenue, Boston, MA 02215-1610, USA.
- 3College of Pharmacy, Western University, California Campus, 309 E. Second St., Pomona, CA 91766-1854, USA.
- 4Department of Psychiatry, Boston University Chobanian & Avedisian School of Medicine, 72 East Concord Street, Boston, MA 02118-2526, USA.
- 5The Biomedical Genetics Section, Department of Medicine, Boston University Chobanian & Avedisian School of Medicine, 72 East Concord Street, Boston, MA 02118-2526, USA.
Abstract
N⁶-methyladenosine (m⁶A), the most prevalent internal modification in eukaryotic RNA, has emerged as a key epitranscriptomic regulator in the central nervous system, coordinating gene expression programs that govern neural development, synaptic plasticity, and neuronal adaptation throughout the lifespan. This review synthesizes emerging evidence that m⁶A dysregulation represents a shared epitranscriptomic mechanism linking neurodevelopmental and neurodegenerative disorders, highlighting a mechanistic convergence that bridges these traditionally distinct disease categories. Dysregulation of m⁶A-mediated control of neurogenesis, synaptic maturation, and dopaminergic development has been implicated in neurodevelopmental disorders, including autism spectrum disorder, attention-deficit/hyperactivity disorder, and intellectual disability. In neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and Huntington's disease, m⁶A dysregulation mediates multiple interconnected pathogenic processes, including neuroinflammation, mitochondrial dysfunction, tau hyperphosphorylation and aggregation, α-synuclein dysregulation, and impaired neuronal repair. Environmental stressors and metabolic perturbations modulate m⁶A modification patterns, suggesting that gene-environment interactions contribute to disease susceptibility through epitranscriptomic mechanisms. m⁶A modification functions as a dynamic molecular switch governing neural plasticity and circuit function across early development, adulthood, and aging, and its dysregulation predisposes individuals to neurological disease manifestation throughout the lifespan. Advances in cell-type-specific and circuit-resolved m⁶A profiling will deepen our understanding of m⁶A dysregulation and strengthen its translational potential as both a diagnostic biomarker and a therapeutic target in neurological diseases. Furthermore, we evaluate pharmacological and molecular strategies targeting m⁶A regulatory machinery, including the writers METTL3/METTL14, the erasers FTO/ALKBH5, and reader proteins, as promising therapeutic approaches to restore aberrant neuronal circuit function in neurodevelopmental and neurodegenerative disorders.
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BibTeX
@article{ngo2026dynamic,
title = {{Dynamic m⁶A Methylation in Neurodevelopmental and Neurodegenerative Disorders.}},
author = {Ambrose Loc Ngo and Xuemei Qu and Niki Gharavi Alkhansari and Linda Nguyen and Uyen Tam Nguyen and Huiping Zhang},
journal = {Epigenomes},
year = {2026},
month = oct,
doi = {10.3390/epigenomes10040062},
url = {https://europepmc.org/article/MED/42924721},
note = {CC BY},
}
RIS
TY - JOUR
TI - Dynamic m⁶A Methylation in Neurodevelopmental and Neurodegenerative Disorders.
AU - Ambrose Loc Ngo
AU - Xuemei Qu
AU - Niki Gharavi Alkhansari
AU - Linda Nguyen
AU - Uyen Tam Nguyen
AU - Huiping Zhang
PY - 2026
DA - 2026/10/03
JO - Epigenomes
DO - 10.3390/epigenomes10040062
UR - https://europepmc.org/article/MED/42924721
AB - N⁶-methyladenosine (m⁶A), the most prevalent internal modification in eukaryotic RNA, has emerged as a key epitranscriptomic regulator in the central nervous system, coordinating gene expression programs that govern neural development, synaptic plasticity, and neuronal adaptation throughout the lifespan. This review synthesizes emerging evidence that m⁶A dysregulation represents a shared epitranscriptomic mechanism linking neurodevelopmental and neurodegenerative disorders, highlighting a mechanistic convergence that bridges these traditionally distinct disease categories. Dysregulation of m⁶A-mediated control of neurogenesis, synaptic maturation, and dopaminergic development has been implicated in neurodevelopmental disorders, including autism spectrum disorder, attention-deficit/hyperactivity disorder, and intellectual disability. In neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and Huntington's disease, m⁶A dysregulation mediates multiple interconnected pathogenic processes, including neuroinflammation, mitochondrial dysfunction, tau hyperphosphorylation and aggregation, α-synuclein dysregulation, and impaired neuronal repair. Environmental stressors and metabolic perturbations modulate m⁶A modification patterns, suggesting that gene-environment interactions contribute to disease susceptibility through epitranscriptomic mechanisms. m⁶A modification functions as a dynamic molecular switch governing neural plasticity and circuit function across early development, adulthood, and aging, and its dysregulation predisposes individuals to neurological disease manifestation throughout the lifespan. Advances in cell-type-specific and circuit-resolved m⁶A profiling will deepen our understanding of m⁶A dysregulation and strengthen its translational potential as both a diagnostic biomarker and a therapeutic target in neurological diseases. Furthermore, we evaluate pharmacological and molecular strategies targeting m⁶A regulatory machinery, including the writers METTL3/METTL14, the erasers FTO/ALKBH5, and reader proteins, as promising therapeutic approaches to restore aberrant neuronal circuit function in neurodevelopmental and neurodegenerative disorders.
SN - 2075-4655
ER -