Transcript No Slide Title

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
•
•
•
•
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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)