Research Interests:

The Hensley laboratory for neuropathology research studies the process of neuroinflammation with the goal of identifying conceptually novel protein or pathway targets that might be rationally exploited for neurodisease therapy development.

Neuroinflammation is a specific type of innate immune response that occurs in the brain during many, perhaps all, neurodegenerative diseases (including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease and various motor neuron diseases). Neuroinflammation is manifest by activation of microglial cells in response to dysregulated cytokine networks and may be triggered by deposits of toxic protein or dead cell debris. For instance, amyloid peptides trigger a neuroinflammatory reaction in the Alzheimer’s disease-afflicted brain. Other proteins are implicated in other diseases, and different brain regions are affected, but the biochemical principles are very similar. Normally, microglia remove dead cells and pre-cancerous cells, but when triggered into a neuroinflammatory state the microglia attack neurons either directly or through “collateral damage”. The activated microglia release a host of toxic agents, especially free radicals (such as nitric oxide) that interfere with healthy neuron function.

Our main tool for studying neuroinflammation is the SOD1G93A transgenic mouse, which carries the human gene mutation responsible for hereditary amyotrophic lateral sclerosis (ALS, or Lou Gehrig’s disease). In this animal, the motor neurons of the brain and spinal cord deteriorate at 3-4 months of age and the mouse becomes paralyzed. We have developed a model for ALS pathogenesis in which a cytokine called TNFa drives the neuroinflammatory reaction. In addition to SOD1G93A mouse, we also use mammalian cell culture extensively in our research. Our cell culture tools include chick primary dorsal root ganglia (sensory) neurons; primary astrocytes; and EOC-20 murine microglia.

The most exciting recent outcome of our work was the discovery that an unusual central nervous system (CNS) metabolite called lanthionine ketimine (LK) possesses potent neuroprotective and neurotrophic effects mediated, in part, through a novel binding interaction with the brain protein CRMP2 (collapsing response mediator protein-2) (J. Neuroscience 2010). A cell-permeable LK-ethyl ester (LKE, invented in our lab and granted U.S. patent 7,683,055 in 2010) promotes neurite elongation in primary cell culture at low nanomolar concentrations. Furthermore, LKE protects neurons against glutamate or H2O2; suppresses microglial activation by TNFa; and protects motor neurons from microglial toxicity, all of which activities would benefit CNS tissue afflicted by ALS. We recently published that LKE slows disease progression in the SOD1G93A mouse model of ALS when administered late in the disease (Molecules 2010).

Due to its novel apparent mechanism of CRMP2 action, LKE potentially could become a “first-in-class” drug for treating neurodegeneration in ALS and other conditions. We are aggressively studying LKE and CRMP2 in order to address key questions: What is the metabolic origin of LK? How does LK affect CRMP2 to promote healthy neuron structure and function? What other molecules might bind CRMP2? What other pharmacological tactics might be employed to modulate CRMP2 pathways for therapeutic benefit? We are also collaborating with a number of groups in order to ascertain the full range of neurodegenerative conditions that might be amenable to treatment with LKE and similar CRMP2-binding agents, and to conduct crucial proof-of-concept studies that we hope will lead eventually to clinical development of these novel small molecule therapeutic candidates. Dr. Hensley's work on ALS has been highlighted by the Muscular Dystrophy Association.