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ALS Research Yesterday, Today and Tomorrow

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 Research Yesterday, Today and Tomorrow

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  1. ALS ResearchYesterday, Today and Tomorrow Heather D. Durham, PhD

  2. 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?

  3. Relaying Messages in the Motor System To muscle

  4. What Happens to Motor Neurons in ALS Healthy and Happy Sick and Dysfunctional

  5. 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

  6. Experimental Models of ALS • neuropathology • surrogate tissue • imaging • clinical trials The real thing ALS patients Mouse models Invivo Exvivo

  7. Experimental Models of ALS Tissue Culture Primary spinal cordculture Cell lines In vitro analysis

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

  9. Motor Neuron HealthA Question of Balance DEFENCE MECHANISMS STRESS

  10. 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

  11. Relaying Messages in the Motor System To muscle

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

  13. 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

  14. 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)

  15. Motor Neuron HealthThe Holistic View

  16. 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)

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