Pl. Dejager et N. Heintz, THE LURCHER MUTATION AND IONOTROPIC GLUTAMATE RECEPTORS - CONTRIBUTIONS TO PROGRAMMED NEURONAL DEATH IN-VIVO, Brain pathology, 8(4), 1998, pp. 795-807
The recent positional cloning and physiological characterization of th
e lurcher mutation resulted in the identification of a novel stimulus
that results in neurodegeneration. The catastrophic loss of cerebellar
Purkinje cells in lurcher heterozygotes has now been strongly associa
ted with a large constitutive inward current which ultimately activate
s a programmed form of neuronal death. The completely penetrant and fo
cal nature of the lurcher phenotype gives us an opportunity to investi
gate the manner in which neurons respond to an aberrant signal in the
context of the brain parenchyma, Although there is no human genetic di
sease that is equivalent to the lurcher mutation at this time, its tri
ggering of programmed neuronal death enables us to pose and address qu
estions that are relevant to a large number of human neurological dise
ases, The advantage of working in a genetically manipulable in vivo ma
mmalian system is evident: we can address questions relating to gene f
unction in the nervous system in a context that is physiological. Clas
sical genetic analyses looking for molecules that suppress or modify t
he lurcher phenotype are under way and have now been supplemented with
two novel techniques developed in our laboratory: biolistic transfect
ion of cerebellar slices and Bacterial Artificial Chromosome modificat
ion, The integration of these novel and classical approaches will faci
litate the testing of hypotheses, developed during the course of our s
tudy of the lurcher mutation, which explore the propagation of abnorma
l signals and the initiation of programmed neuronal death in neurons.