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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 Happy Sick 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 • neuropathology • surrogate tissue • imaging • clinical trials The real thing ALS patients Mouse models In vivo Ex vivo Experimental Models of ALS Tissue Culture Primary spinal cord culture In vitro analysis Cell lines 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 Physiological Environmental Pathological Poor Defenses Stress Response Antioxidants Metal-binding proteins Calcium-binding proteins Stress Proteins Trophic factors Anti-apoptotic factors Relaying Messages in the Motor System To muscle Chemical Neurotransmission at the Synapse (Release ... React ... Recycle) astrocyte Gln presynaptic terminal glutamate glutamate transporter glutamate receptors motor neuron Excitotoxicity Hypothesis of ALS (Too much excitement isn't good for you!) astrocyte Gln presynaptic terminal X motor neuron Ca++ ROS glutamate glutamate transporter GLT-1 receptors Even Normal Excitement may be too Hot to Handle! astrocyte Gln motor neuron presynaptic terminal mutant SOD-1 glutamate glutamate transporter glutamate receptors Riluzole Protects Motor Neurons by Reducing Excitement astrocyte Gln presynaptic terminal motor neuron X mutant SOD-1 glutamate GLT-1 transporter glutamate receptors Block Glutamate Receptors and Protect Motor Neurons (But no excitement, no action!) astrocyte Gln presynaptic terminal motor neuron X mutant SOD-1 glutamate glutamate transporter glutamate receptors 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 Genetic Factors Lifestyle Factors Health of other organ systems Environmental Factors Protective mechanisms within motor neurons Interactions of motor neurons with other cells Research Funded By: 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)
