METTL3-dependent RNA m6A dysregulation contributes to neurodegeneration in Alzheimer’s disease through aberrant cell cycle events DOI Creative Commons
Fanpeng Zhao, Ying Xu,

Shichao Gao

et al.

Molecular Neurodegeneration, Journal Year: 2021, Volume and Issue: 16(1)

Published: Sept. 30, 2021

N6-methyladenosine (m6A) modification of RNA influences fundamental aspects metabolism and m6A dysregulation is implicated in various human diseases. In this study, we explored the potential role pathogenesis Alzheimer disease (AD).We investigated expression regulators brain tissues AD patients determined impact underlying mechanism manipulated levels on AD-related deficits both vitro vivo.We found decreased neuronal along with significantly reduced methyltransferase like 3 (METTL3) brains. Interestingly, hippocampus caused by METTL3 knockdown led to significant memory deficits, accompanied extensive synaptic loss death multiple cellular alterations including oxidative stress aberrant cell cycle events vivo. Inhibition or alleviated shMettl3-induced apoptotic activation damage primary neurons. Restored inhibiting its demethylation rescued abnormal events, induced knockdown. Soluble Aβ oligomers exacerbated while overexpression Aβ-induced PSD95 vitro. Importantly, cognitive impairment vivo.Collectively, these data suggested that reduction-mediated likely contributes neurodegeneration which may be a therapeutic target for AD.

Language: Английский

Discovery of Small Molecules that Activate RNA Methylation through Cooperative Binding to the METTL3-14-WTAP Complex Active Site DOI Creative Commons
Simona Selberg, Daria Blokhina, Maria Aatonen

et al.

Cell Reports, Journal Year: 2019, Volume and Issue: 26(13), P. 3762 - 3771.e5

Published: March 1, 2019

Chemical modifications of RNA provide an additional, epitranscriptomic, level control over cellular functions. N-6-methylated adenosines (m6As) are found in several types RNA, and their amounts regulated by methyltransferases demethylases. One the most important enzymes catalyzing generation m6A on mRNA is trimer N-6-methyltransferase METTL3-14-WTAP complex. Its activity has been linked to such critical biological processes as cell differentiation, proliferation, death.We used silico-based discovery identify small-molecule ligands that bind determined experimentally binding affinity kinetics, well effect enzymatic function. We show these serve activators

Language: Английский

Citations

158
Regulation of axonal regeneration after mammalian spinal cord injury DOI
Binhai Zheng, Mark H. Tuszynski

Nature Reviews Molecular Cell Biology, Journal Year: 2023, Volume and Issue: 24(6), P. 396 - 413

Published: Jan. 5, 2023

Language: Английский

Citations

151
The role of m6A modification in physiology and disease DOI Creative Commons
Chuan Yang, Yiyang Hu, Bo Zhou

et al.

Cell Death and Disease, Journal Year: 2020, Volume and Issue: 11(11)

Published: Nov. 8, 2020

Abstract Similar to DNA epigenetic modifications, multiple reversible chemical modifications on RNAs have been uncovered in a new layer of modification. N6-methyladenosine (m 6 A), modification that occurs ~30% transcripts, is dynamically regulated by writer complex (methylase) and eraser (RNA demethylase) proteins, recognized reader A-binding) proteins. The effects m A are reflected the functional modulation mRNA splicing, export, localization, translation, stability regulating RNA structure interactions between RNA-binding This involved variety physiological behaviors, including neurodevelopment, immunoregulation, cellular differentiation. disruption modulations impairs gene expression function ultimately leads diseases such as cancer, psychiatric disorders, metabolic disease. review focuses mechanisms functions behaviors diseases.

Language: Английский

Citations

146
Axon Regeneration in the Mammalian Optic Nerve DOI
Philip R. Williams, Larry I. Benowitz, Jeffrey L. Goldberg

et al.

Annual Review of Vision Science, Journal Year: 2020, Volume and Issue: 6(1), P. 195 - 213

Published: Sept. 15, 2020

The damage or loss of retinal ganglion cells (RGCs) and their axons accounts for the visual functional defects observed after traumatic injury, in degenerative diseases such as glaucoma, compressive optic neuropathies from glioma. By using nerve crush injury models, recent studies have revealed cellular molecular logic behind regenerative failure injured RGC adult mammals suggested several strategies with translational potential. This review summarizes these findings discusses challenges developing clinically applicable neural repair strategies.

Language: Английский

Citations

141
METTL3-dependent RNA m6A dysregulation contributes to neurodegeneration in Alzheimer’s disease through aberrant cell cycle events DOI Creative Commons
Fanpeng Zhao, Ying Xu,

Shichao Gao

et al.

Molecular Neurodegeneration, Journal Year: 2021, Volume and Issue: 16(1)

Published: Sept. 30, 2021

N6-methyladenosine (m6A) modification of RNA influences fundamental aspects metabolism and m6A dysregulation is implicated in various human diseases. In this study, we explored the potential role pathogenesis Alzheimer disease (AD).We investigated expression regulators brain tissues AD patients determined impact underlying mechanism manipulated levels on AD-related deficits both vitro vivo.We found decreased neuronal along with significantly reduced methyltransferase like 3 (METTL3) brains. Interestingly, hippocampus caused by METTL3 knockdown led to significant memory deficits, accompanied extensive synaptic loss death multiple cellular alterations including oxidative stress aberrant cell cycle events vivo. Inhibition or alleviated shMettl3-induced apoptotic activation damage primary neurons. Restored inhibiting its demethylation rescued abnormal events, induced knockdown. Soluble Aβ oligomers exacerbated while overexpression Aβ-induced PSD95 vitro. Importantly, cognitive impairment vivo.Collectively, these data suggested that reduction-mediated likely contributes neurodegeneration which may be a therapeutic target for AD.

Language: Английский

Citations

138