Neuronal ceroid lipofuscinoses.

The neuronal ceroid lipofuscinoses (NCL) are severe neurodegenerative lysosomal storage disorders of childhood, characterized by accumulation of autofluorescent ceroid lipopigments in most cells. NCLs are caused by mutations in at least ten recessively inherited human genes, eight of which have been characterized. The NCL genes encode soluble and transmembrane proteins, localized to the endoplasmic reticulum (ER) or the endosomal/lysosomal organelles. The precise function of most of the NCL proteins has remained elusive, although they are anticipated to carry pivotal roles in the central nervous system. Common clinical features in NCL, including retinopathy, motor abnormalities, epilepsia and dementia, also suggest that the proteins may be functionally linked. All subtypes of NCLs present with selective neurodegeneration in the cerebral and cerebellar cortices. Animal models have provided valuable data about the pathological characteristics of NCL and revealed that early glial activation precedes neuron loss in the thalamocortical system. The mouse models have also been efficiently utilized for the evaluation of therapeutic strategies. The tools generated by the accomplishments in genomics have further substantiated global analyses and these have initially provided new insights into the NCL field. This review summarizes the current knowledge of the NCL proteins, basic characteristics of each disease and studies of pathogenetic mechanisms in animal models of these diseases.