Rac1 impairs retinal axon degeneration via Kif2a in a mouse model of chronic ocular hypertension

Rac1, a member of the small G protein Rho family, has been implicated in neurodegenerative diseases. Degeneration of neuronal soma and axon belongs to active autonomous processes that involve different molecular mechanisms. We have previously demonstrated that Rac1 deletion prevents retinal ganglion cells from glaucomatous injury; however, its role in axon degeneration is not fully understood. In this study, we found that activation of Rac1 exacerbated axonal transport damage in an experimental glaucoma model. Inhibiting Rac1 activity by genetic or pharmacological methods alleviated the dysfunction of axonal transport and improved the integrity of microtubules by up-regulating the expression of β-III tubulin and myelin basic protein. Rac1 interacted with Sirt1, a key molecule of Wallerian degeneration, which regulated the activity of Rac1 and its downstream molecule PAK1. Furthermore, Rac1 modulated Kif motors at the transcriptional level, among which Kif2a, a lysosome-localization regulator, was negatively regulated by Rac1. Intravitreal injection of Kif2a siRNA reversed the improvement of Rac1 inhibition-mediated axonal transport by reducing autolysosomes. Our results suggest that Rac1/Kif2a accelerates the process of retinal ganglion cell axon degeneration by impairing the autophagic flux in glaucoma, which may be an intriguing therapy target for glaucoma.