Neuronal ceroid lipofuscinosis (NCL), also known as
Batten disease, is a debilitating
neurological disorder that affects both children and adults. Thirteen genetically distinct genes have been identified that when mutated, result in abnormal lysosomal function and an excessive accumulation of
ceroid lipofuscin in neurons, as well as other cell types outside of the central nervous system. The NCL family of
proteins is comprised of lysosomal
enzymes (PPT1/CLN1, TPP1/CLN2, CTSD/CLN10, CTSF/CLN13),
proteins that peripherally associate with membranes (DNAJC5/CLN4, KCTD7/CLN14), a soluble lysosomal
protein (CLN5), a
protein present in the secretory pathway (PGRN/CLN11), and several
proteins that display different subcellular localizations (CLN3, CLN6, MFSD8/CLN7, CLN8, ATP13A2/CLN12). Unfortunately, the precise functions of many of the NCL
proteins are still unclear, which has made targeted
therapy development challenging. The social amoeba Dictyostelium discoideum has emerged as an excellent model system for studying the normal functions of
proteins linked to human
neurological disorders. Intriguingly, the genome of this eukaryotic soil microbe encodes homologs of 11 of the 13 known genes linked to NCL. The genetic tractability of the organism, combined with its unique life cycle, makes Dictyostelium an attractive model system for studying the functions of NCL
proteins. Moreover, the ability of human NCL
proteins to rescue gene-deficiency phenotypes in Dictyostelium suggests that the
biological pathways regulating NCL
protein function are likely conserved from Dictyostelium to human. In this review, I will discuss each of the NCL homologs in Dictyostelium in turn and describe how future studies can exploit the advantages of the system by testing new hypotheses that may ultimately lead to effective
therapy options for this devastating and currently untreatable
neurological disorder.