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Promoting axon regeneration by inhibiting RNA N6-methyladenosine demethylase ALKBH5.


ABSTRACT: A key limiting factor of successful axon regeneration is the intrinsic regenerative ability in both the peripheral nervous system (PNS) and central nervous system (CNS). Previous studies have identified intrinsic regenerative ability regulators that act on gene expression in injured neurons. However, it is less known whether RNA modifications play a role in this process. Here, we systematically screened the functions of all common m6A modification-related enzymes in axon regeneration and report ALKBH5, an evolutionarily conserved RNA m6A demethylase, as a regulator of axonal regeneration in rodents. In PNS, knockdown of ALKBH5 enhanced sensory axonal regeneration, whereas overexpressing ALKBH5 impaired axonal regeneration in an m6A-dependent manner. Mechanistically, ALKBH5 increased the stability of Lpin2 mRNA and thus limited regenerative growth associated lipid metabolism in dorsal root ganglion neurons. Moreover, in CNS, knockdown of ALKBH5 enhanced the survival and axonal regeneration of retinal ganglion cells after optic nerve injury. Together, our results suggest a novel mechanism regulating axon regeneration and point ALKBH5 as a potential target for promoting axon regeneration in both PNS and CNS.

SUBMITTER: Wang D 

PROVIDER: S-EPMC10400074 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature

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Promoting axon regeneration by inhibiting RNA N6-methyladenosine demethylase ALKBH5.

Wang Dong D   Zheng Tiemei T   Zhou Songlin S   Liu Mingwen M   Liu Yaobo Y   Gu Xiaosong X   Mao Susu S   Yu Bin B  

eLife 20230803


A key limiting factor of successful axon regeneration is the intrinsic regenerative ability in both the peripheral nervous system (PNS) and central nervous system (CNS). Previous studies have identified intrinsic regenerative ability regulators that act on gene expression in injured neurons. However, it is less known whether RNA modifications play a role in this process. Here, we systematically screened the functions of all common m<sup>6</sup>A modification-related enzymes in axon regeneration  ...[more]

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