The lurcher gene induces apoptotic death in cerebellar Purkinje cells

In the neurologically mutant mouse strain lurcher (Lc), heterozygous animals display cell autonomous degeneration of cerebellar Purkinje cells beginning in the second postnatal week. During the course of our studies to identify the genetic lesion responsible for this disease (Norman et al., 1991), we have formulated an hypothesis suggesting that in Lc Purkinje cells homeostasis is sufficiently perturbed to lead to the activation of programmed cell death, thus resulting in neuronal loss and the consequent neurologic disease (Heintz, 1993). To address this possibility, we have examined the properties of Lc Purkinje cells as they die during the second postnatal week. Our light and electron microscopic studies demonstrate that dying Lc Purkinje cells exhibit the characteristic morphologic features of apoptosis, including nuclear condensation, axon beading and membrane blebbing. Using an in situ end-labeling method, we have also detected nicked nuclear DNA in these cells. Furthermore, we have examined the expression of the sulfated glycoprotein 2 (SGP2), whose mRNA is induced in both T-cells and prostate epithelial cells undergoing apoptotic death. We show by in situ hybridization that SGP2 is not expressed at detectable levels in normal Purkinje cells, but that its mRNA is present in Lc Purkinje cells prior to their death. Also expression of the Kv3.3b potassium channel, which marks the terminal phase of Purkinje cell differentiation, is evident in Lc Purkinje cells prior to their death. These data demonstrate that the Lc mutation induces apoptosis in cerebellar Purkinje cells following their maturation in postnatal cerebellum. Isolation of the Lc mutation and further analysis of its action in eliciting apoptosis can provide an important opportunity for understanding the etiology of neurodegenerative disease.