Advanced Science
·
2026
·
IF 14.1
Yueyang Li,Sifei Yu,Kaidong Lu,Yujie Zhang,Mingjie Dong,Yan Peng,Liang Xue,Waleed Alam,Yuxuan Shui,Yi Zhou,Wuyunhan Ma,Meng Bao,Peiming Li,Peiyi Luo,Tiezhan Lu,Jiajia Li,Kang Zhang,Yuying Wang,Shuchen Yang,Nuoya Yin,Francesco Faiola,Zilong Gao,Jingfeng Zhou,Fei Zhao,Yali He,Magdalena J. Koziol
Amyloid-beta (Aβ) aggregation, mitochondrial dysfunction, and cognitive decline are hallmarks of Alzheimer's disease (AD), but its initiating molecular events remain unknown. Given that RNA modifications regulate neurodevelopment and neurodegeneration, we explore their functional role in 5xFAD mice, an Aβ AD model. We discover that N1-methyladenosine (m1A) is the most altered RNA modification, and that its regulator demethylase, ALKBH3 is upregulated. Strikingly, Alkbh3 reduction decreases Aβ plaques and restores cognition. Conversely, elevated ALKBH3 levels, observed in AD patients, compromise neuronal morphology and mitochondrial function by impairing mitophagy (degradation of dysfunctional mitochondria), a known driver of neuronal dysfunction. Mechanistically, we reveal that ALKBH3 removes m1A from PINK1 mRNA, the mitophagy master regulator. Given that ALKBH3 is elevated in human AD, causally linked to mitophagy impairment, and confers neuroprotection when depleted, we present ALKBH3 as a mechanistically validated therapeutic target in AD.
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DOI
PubMed
高影响因子
NUCLEIC ACIDS RESEARCH
·
2022
·Vol. 50
·期 17
·9858-9872
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IF 19.16
You Xue-Jiao,Zhang Shan,Chen Juan-Juan,Tang Feng,He Jingang,Wang Jie,Qi Chu-Bo,Feng Yu-Qi,Yuan Bi-Feng
RNA molecules harbor diverse modifications that play important regulatory roles in a variety of biological processes. Over 150 modifications have been identified in RNA molecules. N6-methyladenosine (m6A) and 1-methyladenosine (m1A) are prevalent modifications occurring in various RNA species of mammals. Apart from the single methylation of adenosine (m6A and m1A), dual methylation modification occurring in the nucleobase of adenosine, such as N6,N6-dimethyladenosine (m6,6A), also has been reported to be present in RNA of mammals. Whether there are other forms of dual methylation modification occurring in the nucleobase of adenosine other than m6,6A remains elusive. Here, we reported the existence of a novel adenosine dual methylation modification, i.e. 1,N6-dimethyladenosine (m1,6A), in tRNAs of living organisms. We confirmed that m1,6A is located at position 58 of tRNAs and is prevalent in mammalian cells and tissues. The measured level of m1,6A ranged from 0.0049% to 0.047% in tRNAs. Furthermore, we demonstrated that TRMT6/61A could catalyze the formation of m1,6A in tRNAs and m1,6A could be demethylated by ALKBH3. Collectively, the discovery of m1,6A expands the diversity of RNA modifications and may elicit a new tRNA modification-mediated gene regulation pathway.
研究领域:
分子生物学
·
表观遗传学
·
生物化学
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高影响因子
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