A small molecule M1 promotes optic nerve regeneration to restore target-specific neural activity and visual function

Research output: Journal Publications and ReviewsRGC 21 - Publication in refereed journalpeer-review

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Detail(s)

Original languageEnglish
Article numbere2121273119
Journal / PublicationProceedings of the National Academy of Sciences of the United States of America
Volume119
Issue number44
Online published28 Oct 2022
Publication statusPublished - 2022

Link(s)

Abstract

Axon regeneration is an energy-demanding process that requires active mitochondrial transport. In contrast to the central nervous system (CNS), axonal mitochondrial transport in regenerating axons of the peripheral nervous system (PNS) increases within hours and sustains for weeks after injury. Yet, little is known about targeting mitochondria in nervous system repair. Here, we report the induction of sustained axon regeneration, neural activities in the superior colliculus (SC), and visual function recovery after optic nerve crush (ONC) by M1, a small molecule that promotes mitochondrial fusion and transport. We demonstrated that M1 enhanced mitochondrial dynamics in cultured neurons and accelerated in vivo axon regeneration in the PNS. Ex vivo time-lapse imaging and kymograph analysis showed that M1 greatly increased mitochondrial length, axonal mitochondrial motility, and transport velocity in peripheral axons of the sciatic nerves. Following ONC, M1 increased the number of axons regenerating through the optic chiasm into multiple subcortical areas and promoted the recovery of local field potentials in the SC after optogenetic stimulation of retinal ganglion cells, resulting in complete recovery of the pupillary light reflex, and restoration of the response to looming visual stimuli was detected. M1 increased the gene expression of mitochondrial fusion proteins and major axonal transport machinery in both the PNS and CNS neurons without inducing inflammatory responses. The knockdown of two key mitochondrial genes, Opa1 or Mfn2, abolished the growth-promoting effects of M1 after ONC, suggesting that maintaining a highly dynamic mitochondrial population in axons is required for successful CNS axon regeneration.

Research Area(s)

  • axon regeneration, mitochondrial dynamics, optic nerve crush, peripheral nerve injury, visual function recovery

Citation Format(s)

A small molecule M1 promotes optic nerve regeneration to restore target-specific neural activity and visual function. / Au, Ngan Pan Bennett; Chand, Raza; Kumar, Gajendra et al.
In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 119, No. 44, e2121273119, 2022.

Research output: Journal Publications and ReviewsRGC 21 - Publication in refereed journalpeer-review

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