Phospholipases and the molecular basis for the formation of ceroid in Batten disease

Lysosomal ceroid/lipofuscinosis storage in human, canine, and ovine forms of neuronal ceroidlipofuscinosis is predominantly in neurons and retinal pigment epithelial cells. Despite problems in identifying individual storage materials, it is believed that non-enzymic oxidation of unsaturated fatty acids in phospholipids and inhibition of lysosomal proteolysis, leading to massive deposition of autofluorescent pigment, is the cause of the disease. We have, therefore, studied cellular phospholipases and find a marked deficiency of lysosomal phospholipase A1 (PLA1) in canine NCL brain. Other lysosomal hydrolases, and cytosolic/mitochondrial forms of phospholipase A2 are completely normal. We believe that the PLA1 deficiency leads to transient lysosomal storage of phospholipids containing peroxy fatty acids which are then chemically converted to hydroxynonenal, a potent inhibitor of a thiol-dependent enzymes. Inhibition of proteases is believed to be intrinsic to the formation of lipofuscin. An inherited deficiency of a thiol protease (the lysosomal cathepsin H) in two siblings with NCL can also lead to build up of peptides which are then cross-linked and converted into ceroid-containing curvilinear bodies. Thus there is evidence for molecular and genetic heterogeneity in Batten disease.