Regenerative Strategies Targeting Retinoic Acid Signaling in Giant Axonal Neuropathy

Univ Of North Carolina Chapel Hill, Chapel Hill NC

Investigators

Abstract

ABSTRACT The molecular and cellular processes that control axonal degeneration in response to genetic mutations are poorly understood, hindering the advancement of regenerative strategies to improve patient outcomes. In the pediatric neurodegenerative disease giant axonal neuropathy (GAN), axons degenerate due to loss-of-function mutations in the gene KLHL16. Current understanding is that gigaxonin, the product of KLHL16, facilitates the proteasomal turnover of cytoskeletal intermediate filament (IF) proteins through its major function as an adaptor between an E3 ubiquitin ligase and the IF substrate. This mechanism explains the progressive accumulation of IF proteins in many cell types of GAN patients, but the reasons behind the selective and profound susceptibility of neurons to KLHL16 mutations are unknown. Seeking to fill this knowledge gap, we made the novel discovery that retinoic acid (RA) signaling is dramatically impaired in GAN patient neurons. RA is a critical molecule involved in nervous system development and regeneration, but its high regenerative potential has not yet been realized in humans. Our team has a unique opportunity to advance RA biology in the context of GAN using a focused approach centered on two disease targets we identified: the cellular retinoid acid binding protein-1 (CRABP1) and the RA receptor β (RARβ). Using a robust and clinically relevant experimental pipeline of GAN patient iPSC-motor neurons and a new humanized GAN mouse models that we developed, this project will examine the novel concept that targeted modulation of RA signaling will enhance axonal regeneration and functional improvement in GAN.