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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?.
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ALS ResearchYesterday, 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 Invivo Exvivo
Experimental Models of ALS Tissue Culture Primary spinal cordculture Cell lines In vitro analysis
Mutant SOD1 Proteins Misfold and Aggregate in Motor Neurons Aggregated Mutant SOD1 Normal Human SOD1
Motor Neuron HealthA Question of Balance DEFENCE MECHANISMS STRESS
Motor Neurons Live on the Edge Poor Defenses Lots of Stress Stress Response Antioxidants Metal-binding proteins Calcium-binding proteins Stress Proteins Trophic factors Anti-apoptotic factors Physiological Environmental Pathological
Relaying Messages in the Motor System To muscle
Boost up the Defensive Line Reduce Stress Antioxidants Energy Boosters Trophic factors Calcium-binding proteins Stress Proteins Anti-apoptotic factors Riluzole Gabapentin Receptor blockers
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)
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)