The use of embryonic neural cell transplants has been shown to be an effective therapy in Parkinson's disease, where the role of the transplant is to replace neurotransmitter (dopamine) which has been lost because of neurodegeneration. Other animal models have demonstrated similar success when the replacement of neurotransmitter is sufficient to alleviate symptoms. The central hypothesis of the present proposal is that grafted neurons can prevent the retrograde transneuronal degeneration of host neurons in a neurodegenerative condition. Under ideal circumstances, such an effect could reduce the severity of the symptoms, and slow or halt disease progression. The present proposal will investigate the potential of neural grafts to rescue host neurons from retrograde transneuronal degeneration in an animal model of hereditary ataxia, the lurcher mutant mouse. Experiments will use embryonic Purkinje cell transplants to the lurcher cerebellum to prevent degeneration in the host inferior olive. Unilateral grafts will be used in order to provide an internal comparison between left and right inferior olivary complexes. Initial experiments will determine the optimal grafting parameters, and will include an investigation of the use of nerve growth factor to enhance graft survival. The synaptic integration and physical relationships of the grafted neurons will be investigated by transmission electron microscopy using both qualitative and quantitative methods. Anterograde tracing of olivocerebellar fibers using Phaseolus vulgaris leucoagglutinin will be used to assess the tropic and trophic effects of grafted Purkinje cells on the host climbing fibers. Such effects will be documented by quantitative analysis of morphological parameters of the olivocerebellar fibers. Comparisons olivary cell number in graft hosts and non-grafted lurcher mice will reveal whether neuronal rescue has occurred, and how many neurons have been saved. Quantitative analysis of the rate of olivary neuron loss in lurcher mutants will be used to assess the efficiency of the grafts in rescuing olivary neurons. If the rescue of olivary neurons by Purkinje cell grafts can be proven, then future experiments will be directed at the identification of the factors responsible for neuronal rescue, and at the behavioral consequences of rescue in this system.
| Heckroth, J A; Hobart, N J; Summers, D (1998) Transplanted neurons alter the course of neurodegenerative disease in Lurcher mutant mice. Exp Neurol 154:336-52 |
| Tolbert, D L; Heckroth, J (1998) Purkinje cell transplants in Shaker mutant rats with hereditary Purkinje cell degeneration and ataxia. Exp Neurol 153:255-67 |
