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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 • • • • • • • 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