ALS Research Yesterday, Today and Tomorrow Heather D. Durham, PhD

Summary What causes ALS and how do we study it? What makes most motor neurons so vulnerable? What is the scientific basis for current and future therapies? What are major research questions?

Relaying Messages in the Motor System To muscle

What Happens to Motor Neurons in ALS Healthy and HappySick and Dysfunctional

Causes of ALS 80-90% sporadic (?) Inherited forms –Mutations in Cu/Zn-superoxide dismutase (SOD1) an enzyme that detoxifies oxygen radicals produced in cells during normal metabolism Mutation does not eliminate antioxidant function, but causes the SOD1 protein to become toxic

Experimental Models of ALS The real thing ALS patients Mouse models In vivoEx vivo neuropathology surrogate tissue imaging clinical trials

Experimental Models of ALS Tissue Culture Cell lines Primary spinal cord culture In vitro analysis

Mutant SOD1 Proteins Misfold and Aggregate in Motor Neurons Normal Human SOD1 Aggregated Mutant SOD1

Motor Neuron Health A Question of Balance STRESS DEFENCE MECHANISMS

Motor Neurons Live on the Edge Lots of Stress Poor Defenses Physiological Environmental Pathological Stress Response Antioxidants Metal-binding proteins Calcium-binding proteins Stress Proteins Trophic factors Anti-apoptotic factors

Relaying Messages in the Motor System To muscle

Boost up the Defensive Line Reduce Stress Riluzole Gabapentin Receptor blockers Antioxidants Energy Boosters Trophic factors Calcium-binding proteins Stress Proteins Anti-apoptotic factors

Other Therapeutic Strategies Prevent Secondary Damage: Motor neurons don’t work alone. Other cells called glia (astrocytes and microglia) can secrete protective molecules, but also toxic substances. –COX-2 inhibitors –Minocycline Attack on Multiple Fronts: Combined therapies Gene Therapy Cell Therapy

Future Research:What we Need Early biomarkers of disease Combined therapies to boost defenses Definition of other genetic causes: more test models Better therapeutic delivery to CNS Understanding of how multiple stresses affect motor neurons Understanding of how ALS affects cells other than motor neurons Understanding of the causes of sporadic ALS (genetic predispositions; influence of environment, aging and lifestyle)

Motor Neuron Health The Holistic View

ALS Society of Canada Muscular Dystrophy Association of Canada Canadian Institutes for Health Research Montreal Neurological Institute /McGill ALS Association of America Muscular Dystrophy Association (USA) Research Funded By: