Reflections on animal models of neurological disorders Marie-Francoise Chesselet UCLA

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 Hereditary One gene 100% penetrance Dominant CAG repeat expansion Huntingtin Parkinson’s disease Mostly sporadic 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 10% Familial Mutations Environment Genetic risk factors LINK SUSPECTED 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