Abstract
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.
Highlights
Dictyostelium as a model system for studying human neurological disorders The social amoeba Dictyostelium discoideum is a fascinating microbe that has emerged as a valuable model organism for biomedical and human disease research
The Neuronal ceroid lipofuscinosis (NCL) family of proteins is comprised of lysosomal enzymes (PPT1/CLN1, Tri-peptidyl peptidase 1 (TPP1)/CLN2, cathepsin D (CTSD)/CLN10, cathepsin F (CTSF)/CLN13), proteins that peripherally associate with membranes (DNAJC5/ CLN4, KCTD7/CLN14), a soluble lysosomal protein
Many of the NCL homologs in Dictyostelium were detected in a proteomic profile of the macropinocytic pathway, which supports the suggestion that NCL proteins share common functions or participate in the same biological pathway or process [32, 119] (Table 4)
Summary
Dictyostelium as a model system for studying human neurological disorders The social amoeba Dictyostelium discoideum is a fascinating microbe that has emerged as a valuable model organism for biomedical and human disease research. The Dictyostelium homolog, cln3, is composed of three exons that encode a 421 amino acid, 47 kDa protein (Cln3; DDB0233983) predicted to contain 10–11 transmembrane domains (Table 2). Like human CLN5, the Dictyostelium homolog contains a signal peptide for secretion (SignalP 4.0) [39] and has been detected in conditioned media from developing cells (Huber, manuscript in preparation).
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