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

The real thingALS patients

Mouse models

In vivo Ex vivo

• neuropathology• surrogate tissue• imaging• clinical trials

Experimental Models of ALS

Tissue Culture

Cell linesPrimary spinal

cord culture

In vitro analysis

Mutant SOD1 Proteins Misfold and Aggregate in Motor Neurons

Normal Human SOD1 Aggregated Mutant SOD1

Motor Neuron HealthA Question of Balance

STRESS DEFENCEMECHANISMS

Motor Neurons Live on the Edge

Lots of Stress Poor Defenses

PhysiologicalEnvironmentalPathological

Stress Response AntioxidantsMetal-binding proteinsCalcium-binding proteins Stress ProteinsTrophic factorsAnti-apoptotic factors

Relaying Messages in the Motor System

To muscle

motor neuron

astrocyte

Chemical Neurotransmission at the SynapseChemical Neurotransmission at the Synapse(Release ... React ... Recycle)(Release ... React ... Recycle)

presynaptic terminal

glutamate

glutamate transporter

Gln

glutamate receptors

motor neuron

astrocyte

Excitotoxicity Hypothesis of ALSExcitotoxicity Hypothesis of ALS(Too much excitement isn't good for you!(Too much excitement isn't good for you!))

presynaptic terminal

glutamate

glutamate transporter

Gln

XCa++

ROS

GLT-1 receptors

motor neuron

astrocyte

Even Normal Excitement may be too Even Normal Excitement may be too Hot to Handle!Hot to Handle!

presynaptic terminal

glutamate

glutamate transporter

glutamate receptors

Gln

mutant SOD-1

motor neuron

astrocyte

Riluzole Protects Motor Neurons by Riluzole Protects Motor Neurons by Reducing ExcitementReducing Excitement

presynaptic terminal

glutamate

GLT-1 transporter

glutamate receptors

Gln

mutant SOD-1

X

motor neuron

astrocyte

Block Glutamate Receptors and Protect Block Glutamate Receptors and Protect Motor NeuronsMotor Neurons

(But no excitement, no action!)(But no excitement, no action!)

presynaptic terminal

glutamate

glutamate transporter

glutamate receptors

Gln

mutant SOD-1

X

Boost up the Defensive Line

Reduce Stress

RiluzoleGabapentinReceptor blockers

AntioxidantsEnergy BoostersTrophic factorsCalcium-binding proteinsStress ProteinsAnti-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)

Genetic Genetic FactorsFactors

Lifestyle Lifestyle FactorsFactors

Environmental Environmental FactorsFactors

Protective Protective mechanisms mechanisms within motor within motor

neuronsneurons

Interactions Interactions of motor of motor

neurons with neurons with other cellsother cells

Health of Health of other organ other organ

systemssystems

Motor Neuron HealthThe 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: