Transcript Reflections on animal models of neurological disorders

Reflections on animal models
of neurological disorders
Marie-Francoise Chesselet
UCLA
[email protected]
Genetic models of
neurodegenerative diseases
• Huntington’s disease
Hereditary
One gene
100% penetrance
Dominant
CAG repeat expansion
Huntingtin
• Parkinson’s disease
Mostly sporadic
Multiple genes
Dominant or recessive
Should a model reproduce all
“key” features of the disease?
• Even mice expressing the HD mutation
show no or late neuronal loss in striatum
• Are they useless?
• Display many early molecular, pathological,
behavioral deficits also seen in the disease
Genetic models of
neurodegenerative diseases
• Huntington’s disease
• Parkinson’s disease
Hereditary
One gene
100% penetrance
Dominant
Mostly sporadic
CAG repeat expansion
Huntingtin
Multiple genes
Dominant or recessive
Use Toxins
instead?
Classical Models of Parkinson’s
Disease:
Injection of toxins that kill dopamine
neurons
• MPTP (mice, primates)
• 6- hydroxydopamine (rats, mice)
• Paraquat (rats, mice)
• Rotenone (rats)
PROBLEM: Neuroprotection in these models
has not predicted clinical efficacy.
PD: Mechanisms
90% Sporadic
Environment
Genetic risk factors
LINK SUSPECTED
10% Familial
Mutations
LINK CERTAIN
Parkinson’s disease affects many
systems
• Akinesia
• Rigidity
• Tremor
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Postural imbalance
Olfactory loss
Cognitive disorders (implicit memory)
Affective disorders (depression/anxiety/apathy)
Sleep disturbances
Autonomic disorders (hypotension)
Digestive symptoms (constipation)
Braak et al. Neurobiol Aging, 2003
Should a model reproduce all
“key” features of the disease?
• What defines the disease in humans may
not be the earliest dysfunction, which may be
important to understand and treat.
Reflections on animal models
of neurological disorders
• Avoid excessive anthropomorphism
• Focus on endophenotypes
• Adapt the model to the question
• Use genetic approaches to test
mechanisms
• Use lesions to test for symptomatic
treatments