Review Dictyostelium, a microbial model for brain disease ☆ S.J. Annesley, S. Chen, L.M. Francione, O. Sanislav, A.J. Chavan, C. Farah, S.W. De Piazza, C.L. Storey, J. Ilievska, S.G. Fernando, P.K. Smith, S.T. Lay, P.R. Fisher ⁎ Department of Microbiology, La Trobe University, Plenty Rd., Bundoora, VIC, Australia, 3086 abstract article info Article history: Received 18 June 2013 Received in revised form 5 October 2013 Accepted 10 October 2013 Available online 23 October 2013 Keywords: Mitochondrial disease Dictyostelium neurodegenerative disease AMPK OXPHOS Lysosomal disease Background: Most neurodegenerative diseases are associated with mitochondrial dysfunction. In humans, mutations in mitochondrial genes result in a range of phenotypic outcomes which do not correlate well with the underlying genetic cause. Other neurodegenerative diseases are caused by mutations that affect the function and trafficking of lysosomes, endosomes and autophagosomes. Many of the complexities of these human diseases can be avoided by studying them in the simple eukaryotic model Dictyostelium discoideum. Scope of review: This review describes research using Dictyostelium to study cytopathological pathways underlying a variety of neurodegenerative diseases including mitochondrial, lysosomal and vesicle trafficking disorders. Major conclusions: Generalised mitochondrial respiratory deficiencies in Dictyostelium produce a consistent pattern of defective phenotypes that are caused by chronic activation of a cellular energy sensor AMPK (AMP- activated protein kinase) and not ATP deficiency per se. Surprisingly, when individual subunits of Complex I are knocked out, both AMPK-dependent and AMPK-independent, subunit-specific phenotypes are observed. Many nonmitochondrial proteins associated with neurological disorders have homologues in Dictyostelium and are associated with the function and trafficking of lysosomes and endosomes. Conversely, some genes associated with neurodegenerative disorders do not have homologues in Dictyostelium and this provides a unique avenue for studying these mutated proteins in the absence of endogeneous protein. General significance: Using the Dictyostelium model we have gained insights into the sublethal cytopathological pathways whose dysregulation contributes to phenotypic outcomes in neurodegenerative disease. This work is beginning to distinguish correlation, cause and effect in the complex network of cross talk between the various organelles involved. This article is part of a Special Issue entitled Frontiers of Mitochondrial Research © 2013 Elsevier B.V. All rights reserved. 1. Introduction — the value of the Dictyostelium model D. discoideum is a social amoeba or cellular slime mould that has long been regarded as a valuable eukaryotic model organism for the study of many signalling processes, including those leading to chemotactic motility and regulation of the actinomyosin cytoskeleton. The reasons for Dictyostelium's success as a model are numerous. Firstly the complete genome of D. discoideum has been sequenced [1], it is genetically tractable, readily grown clonally as a eukaryotic microorganism and is highly accessible for biochemical, cell biological and physiological studies. These properties are shared with other microbial model organ- isms. What sets Dictyostelium apart from the other systems is its unique lifecycle with motile unicellular and multicellular stages and multiple cell types (Fig. 1). These offer for study an unparalleled variety of phenotypes which serve as accessible “readouts” of the associated signalling pathways. Dictyostelium lives as an amoeba in the soil of temperate forests, feeding by phagocytosis of microorganisms (laboratory strains can also survive by macropinocytosis of liquid nutrients) [2]. When the food source is depleted the amoebae differentiate and begin to emit pulses of cAMP to which they are now attracted, resulting in the aggregation of approximately 100,000 cells. These cells then undergo a multicellular developmental programme in which the cells differentiate into two main cell types, prestalk and prespore cells that are predestined to form the stalk and spores of a multicellular fruiting body (Fig. 1A). Aggregation initially produces a mound of cells that then forms a motile organism called a slug, which is composed of multiple cell types organised into different tissues recognisable on the basis of differential gene expression [3,4] (Fig. 1B). From the rear to the front of the slug these are 1. a small rearguard region (ca. 5% of the cells) with a concentration of anterior-like cells (ALC) predestined to form the basal disc, 2. a prespore region in most of the posterior portion of the slug (ca. 70% of the cells), and Biochimica et Biophysica Acta 1840 (2014) 1413–1432 ☆ This article is part of a Special Issue entitled Frontiers of Mitochondrial Research. ⁎ Corresponding author at: Department of Microbiology La Trobe University, VIC 3086, Australia. Tel.: +61 3 94792229: fax: +61 3 94791222. E-mail address: P.Fisher@latrobe.edu.au (P.R. Fisher). 0304-4165/$ – see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.bbagen.2013.10.019 Contents lists available at ScienceDirect Biochimica et Biophysica Acta journal homepage: www.elsevier.com/locate/bbagen