Using the social amoeba Dictyostelium to study the functions of proteins linked to neuronal ceroid lipofuscinosis

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.

Calmodulin‐mediated events during the life cycle of the amoebozoan Dictyostelium discoideum

“…(Berchtold & Villalobo, ; Villalobo, ; Urrutia et al, ). The importance of D. discoideum as a model system to investigate fundamental biological processes and disease states is gaining increased attention (Annesley & Fisher, ; Huber, ; Dunn et al, ; Myre et al, ; Tatischeff, ). Here we show the critical role of CaM and its CaMBPs throughout the full developmental cycle of D. discoideum to emphasize its importance for continued study of specific cellular events and disease processes.…”

“…Initially recognized for studies on fundamental biological processes, more recently it has been used a biomedical model for research into autophagy, cell stress, extracellular vesicles, osmoregulation, wound healing, neurodegenerative diseases, and mitochondrial diseases, among others (e.g. Annesley & Fisher, Annesley & Fisher, 2001;Huber, 2016;Mathavarajah, O'Day, & Huber, 2018b;Dunn et al, 2018;Myre, Huber, & O'Day, 2018;Tatischeff, 2019).…”

Methods to Monitor and Quantify Autophagy in the Social Amoeba Dictyostelium discoideum

“…For example, research on Dictyostelium has contributed to the unraveling of the signaling pathways implicated in the poorly defined therapeutic effects of valproic acid and lithium [ 18 ]. Additionally, Dictyostelium has proven to be a good model organism to address questions regarding the etiology of some human diseases; for instance, orthologues of the genes implicated in neurological disorders such as neuronal ceroid lipofuscinosis [ 21 ], chorea-acanthocytosis [ 22 ], Alzheimer’s disease [ 23 ], and lissencephaly [ 24 ] (among others) have been studied in Dictyostelium , shedding light on the cellular biology underlying these conditions. Further, as many innate immunity mechanisms used by animal phagocytes are conserved in Dictyostelium , studies using this amoeba as a model organism have expanded the knowledge on the molecular mechanisms of infection and pathogen–host interactions [ 20 , 25 ].…”

A Tripeptidyl peptidase 1 is a binding partner of GPHR (Golgi pH regulator) in Dictyostelium

“…Based on these findings, the potential of D. discoideum to contribute to the study of the functions of proteins linked to neuronal ceroid lipofuscinosis is strengthened and can lead to new treatment options ( Huber, 2016 ).…”

“…Finally, a fruiting body consisting of a base, a stalk and a head containing spores is formed. The spores germinate under appropriate conditions and the amoebae initiate a new life cycle ( Huber, 2016 ).…”