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

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.

Real‐time field‐programmable gate array‐based closed‐loop deep brain stimulation platform targeting cerebellar circuitry rescues motor deficits in a mouse model of cerebellar ataxia

“…The signal was then rectified and smoothed by removing the direct current from the raw EMG signal. RMS of EMG amplitude was detected by setting the minimum threshold to 10% above the rising and falling phases of the EMG signal over the time period of 30 s. RMS of EMG amplitude was calculated by taking square root and average of individual points 29,34,35 …”

The next‐generation therapies in ophthalmology for blindness worldwide

“…Gene therapy for glaucoma naturally targets the ciliary epithelium [150][151][152], trabecular reticulum cells [153], and RGCs [154][155][156]. The development of gene therapy for glaucoma is predicated based on the ongoing investigation into its pathogenic etiology and disease pathways, with the identification of a novel gene target hinging upon its pivotal role in regulating RGC apoptosis or ON atrophy associated with glaucoma [157,158] The most common genetic disorder in optic neuropathy is Leber's hereditary optic neuropathy (LHON), which is characterized by progressive degeneration of RGCs [159]. A common mitochondrial DNA mutation in the gene encoding NADH dehydrogenase is responsible for about 60%-90% of occurrences in individuals with LHON [160], and LHON is an ideal disease model for gene therapy research due to its substantial patient population and amenability to correction of the underlying genetic defect [109].…”

“…Gene therapy for glaucoma naturally targets the ciliary epithelium [150–152], trabecular reticulum cells [153], and RGCs [154–156]. The development of gene therapy for glaucoma is predicated based on the ongoing investigation into its pathogenic etiology and disease pathways, with the identification of a novel gene target hinging upon its pivotal role in regulating RGC apoptosis or ON atrophy associated with glaucoma [157, 158]. The CaMKII (calcium/calmodulin protein‐dependent protein kinase II) pathway regulates key cellular processes and functions throughout the body, including those of RGCs.…”

Current understanding of the molecular mechanisms of chemotherapy-induced peripheral neuropathy

“…The results of these studies point to the direction that by maintaining the microtubule dynamics and promoting axonal transport in sensory neurons could protect the patients from axon degeneration and development of CIPN. Our previous study demonstrated that mitochondrial fusion promoter M1 promoted mitochondrial trafficking in the DRG neurons as well as in sciatic nerves leading to a remarkable axon regeneration (an energy-demanding process that requires robust mitochondrial transport along the regenerating axons) after peripheral nerve and optic nerve injuries ( Au et al, 2022a ).…”