A hydrocortisone derivative binds to GAPDH and reduces the toxicity of extracellular polyglutamine-containing aggregates

Abstract

Huntington's disease (HD) has been recently shown to have a horizontally transmitted, prion-like pathology. Thus, the migration of polyglutamine-containing aggregates to acceptor cells is important for the progression of HD. These aggregates contain glyceraldehyde-3-phosphate dehydrogenase (GAPDH), which increases their intracellular transport and their toxicity. Here, we show that RX624, a derivative of hydrocortisone that binds to GAPDH, prevents the formation of aggregates of GAPDH-polyglutamine excreted into the culture medium by PC-12 rat cells expressing mutant huntingtin. RX624 was previously shown to be unable to penetrate cells and, thus, its principal therapeutic action might be the inhibition of polyglutamine-GAPDH complex aggregation in the extracellular matrix. The administration of RX624 to SH-SY5Y acceptor cells that incubated in conditioned medium from PC-12 cells expressing mutant huntingtin caused an approximately 20% increase in survival. This suggests that RX624 might be useful as a drug against polyglutamine pathologies, and that is could be administered exogenously without affecting target cell physiology. This protective effect was validated by the similar effect of an anti-GAPDH specific antibody.

Keywords: Glyceraldehyde-3-phosphate dehydrogenase; Huntington disease; Hydrocortisone 21-hemisuccinate (PubChem CID: 3643); Toxic extracellular aggregates; polyQ.