Cathepsin Deficiency as a Model for Neuronal Ceroid Lipofuscinoses

Abstract

Lysosomal storage disorders arise from genetic alterations in lysosomal function and result in the aberrant accumulation of undigested lipoproteins.1 Neuronal ceroid lipofuscinoses (NCL), collectively known as Batten disease, are autosomal recessive and classical lysosomal storage disorders and are the most common human pediatric neurodegenerative diseases, occurring in 4 to 8 of every 100,000 children.2 NCL is a progressive and fatal neurodegenerative disease currently lacking any effective treatment or cure, thus underscoring the need for a greater understanding of its pathophysiology. In this issue of The American Journal of Pathology, Koike and colleagues3 elegantly describe how the cathepsin D (CD)-deficient mouse and the combined cathepsins B and L (CB/CL)-deficient mouse share neuropathological features common to NCL. Although mutations and/or deficiencies in cathepsins have not been described clinically in NCL, striking similarities exist in the neuropathology of these mice compared to established mouse models of NCL and to human NCL, suggesting involvement of similar neurodegenerative pathways. Previous reports of cell death in NCL have focused on apoptotic cell death as its principal death pathway. However, other death pathways also appear to be involved. Cell death has been defined previously by morphological criteria as either type I apoptotic or type II autophagic.4 Apoptotic death is regulated by pro- and anti-apoptotic members of the Bcl-2 family5 and culminates in the activation of caspases, which are responsible for causing the nuclear condensation, DNA fragmentation, and cell shrinkage that characterize apoptotic morphology.4 Autophagy is a normal cellular process whereby cytoplasmic material and organelles are shuttled to the lysosomes by a complex, regulated series of vesicle fusion events for degradation and ultimate recycling of lysosomal contents.6 Autophagic death is defined morphologically by the aberrant accumulation of autophagic vacuoles in a degenerating cell that in addition often displays morphological features of apoptosis.4 In agreement with such mechanisms, reports from Koike and colleagues,3,7 and Nakanishi and colleagues8 indicate the contribution of both apoptotic and autophagic neuron death, suggesting an interrelationship between these two pathways in neuron death and neurodegeneration in NCL.