Biochemistry of neuronal ceroid lipofuscinoses

This chapter summarizes the recent advances that have been made with respect to biochemical characterization of the neurodegenerative diseases collectively known as neuronal ceroid lipofuscinoses (NCL) or Batten disease. Genomic and proteomic approaches have presently identified eight different forms of NCL (namely, CLN1 through CLN8) based on mutations in specific genes. CLN1 and CLN2 are caused by mutations in genes that encodes lysosomal enzymes,palmitoyl protein thioesterase and pepstatin-insensitive proteinase, respectively. The protein involved in the etiology of CLN3 is a highly hydrophobic, presumably transmembrane protein. NCL are considered as lysosomal storage diseases because of the accumulation of autofluorescent inclusion bodies. The composition of inclusion bodies varies in different forms of the NCL. The major storage component in CLN2 is the subunit c of mitochondrial ATP synthase complex and its accumulation is the direct result of lack of CLN2p in this disease. Mannose-6-phosphorylated glycoproteins accumulate in CLN3 and most likely their accumulation is the result of an intrinsic activity of the CLN3 protein. Significant levels of oligosaccharyl diphosphodolichol also accumulate in CLN3 and CLN2, whereas lysosomal sphingolipid activator proteins (saposins A and D) constitute major component of the storage material in CLN 1. The issue of selective loss of neuronal and retinal cells in NCL still remains to be addressed. Identification of natural substrates for the various enzymes involved in NCL may help in the characterization of the cytotoxic factor(s) and also in designing rationale therapeutic interventions for these group of devastating diseases.