ALS Research Yesterday, Today and Tomorrow

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ALS ResearchYesterday, Today and Tomorrow

• Heather D. Durham, PhD

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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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Relaying Messages in the Motor System
To muscle
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What Happens to Motor Neurons in ALS
Healthy and Happy
Sick and Dysfunctional
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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

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Experimental Models of ALS

• neuropathology
• surrogate tissue
• imaging
• clinical trials

The real thing ALS patients
Mouse models
In vivo
Ex vivo
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Experimental Models of ALS
Tissue Culture
Primary spinal cord culture
Cell lines
In vitro analysis
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Mutant SOD1 Proteins Misfold and Aggregate in
Motor Neurons
Aggregated Mutant SOD1
Normal Human SOD1
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Motor Neuron HealthA Question of Balance
DEFENCE MECHANISMS
STRESS
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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
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Relaying Messages in the Motor System
To muscle
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Boost up the Defensive Line
Reduce Stress
Antioxidants Energy Boosters Trophic
factors Calcium-binding proteins Stress
Proteins Anti-apoptotic factors
Riluzole Gabapentin Receptor blockers
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Other Therapeutic Strategies

• Prevent Secondary Damage Motor neurons dont
  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

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Future ResearchWhat 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)

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Motor Neuron HealthThe Holistic View
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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)