Neuroprotection and axon regeneration by novel low-molecular-weight compounds through the modification of DOCK3 conformation

Abstract

Dedicator of cytokinesis 3 (DOCK3) is an atypical member of the guanine nucleotide exchange factors (GEFs) and plays important roles in neurite outgrowth. DOCK3 forms a complex with Engulfment and cell motility protein 1 (Elmo1) and effectively activates Rac1 and actin dynamics. In this study, we screened 462,169 low-molecular-weight compounds and identified the hit compounds that stimulate the interaction between DOCK3 and Elmo1, and neurite outgrowth in vitro. Some of the derivatives from the hit compound stimulated neuroprotection and axon regeneration in a mouse model of optic nerve injury. Our findings suggest that the low-molecular-weight DOCK3 activators could be a potential therapeutic candidate for treating axonal injury and neurodegenerative diseases including glaucoma.

DOCK3-Associated Neurodevelopmental Disorder—Clinical Features and Molecular Basis

“…Some of these compounds stimulated neuroprotection and axon regeneration in a mouse model of optic nerve injury. These findings may be the basis of the development of new treatments for DOCK3 deficiency using small-molecule compounds that may be more efficient in crossing the BBB [54].…”

“…It remains unclear if a similar process occurs in DOCK3 or other DOCK proteins that bind to both ELMO proteins and RAC1 regulators; however, these studies have laid the foundation for future work in this field. Newer, exciting drug screens for small molecule compounds that modulate DOCK3 conformational changes affecting DOCK3 and ELMO1 interactions have recently been published and could be explored for treating axonal injury and neurodegenerative diseases [36,54].…”