BBB seminar: Kenneth Hensley

Kenneth Hensley
Department of Pathology, University of Toledo, OH, USA

Drug development for the treatment of neurodegenerative diseases has proven particularly difficult. In general we still do not know the pathogenic mechanisms for most neurodegenerative conditions. To the extent that mechanisms are understood, potential drug targets are hidden behind the blood-brain barrier and often share homology to peripheral enzymes or receptors leading to undesirable and dose-limiting off-target effects. Our lab’s approach to neurotherapy has been to research natural systems that the brain uses to gently regulate itself with respect to neuroinflammation and maintenance of healthy axonal structure. This strategy has uncovered the latent therapeutic potential of cyclic thioether ketimines derived from alternative functions of brain transulfuration pathway enzymes. Naturally present at low concentrations in neurons, these metabolites affect numerous processes ranging from autophagy to axon remodeling to microglial activation. Cell and brain-penetrating derivatives of lanthionine ketimine (LK) have shown special promise. These bind to the microtubule-associated adaptor protein collapsin response mediator protein-2 (CRMP2), to subtly alter CRMP2’s interactions with its upstream kinase regulators and downstream pathway effectors. One particular LK-ester derivative (LKE) has shown benefits in diverse mouse models of brain disease including amyotrophic lateral sclerosis (ALS), Alzheimer’s disease (AD), stroke, multiple sclerosis, traumatic brain injury and Batten disease. Despite these potencies, LKE has a wide therapeutic window and causes no adverse effects in rodents, even when administered chronically for one year. Moreover, the study of LKE is serving a discovery function by uncovering new roles for CRMP2 in regulating autophagy and vesicle transport.

Chairperson: Petri Kursula <petri.kursula@uib.no>, Department of Biomedicine