title: Dictyostelium, a microbial model for brain disease.
abstract: 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.
  
  
  METHODS
  This review describes research using Dictyostelium to study cytopathological pathways underlying a variety of neurodegenerative diseases including mitochondrial, lysosomal and vesicle trafficking disorders.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Microbiology, La Trobe University, Plenty Rd., Bundoora, VIC, Australia, 3086.
authors.forename: S J
authors.initials: SJ
authors.lastname: Annesley
authors.affiliation: Department of Microbiology, La Trobe University, Plenty Rd., Bundoora, VIC, Australia, 3086.
authors.forename: S
authors.initials: S
authors.lastname: Chen
authors.affiliation: Department of Microbiology, La Trobe University, Plenty Rd., Bundoora, VIC, Australia, 3086.
authors.forename: L M
authors.initials: LM
authors.lastname: Francione
authors.affiliation: Department of Microbiology, La Trobe University, Plenty Rd., Bundoora, VIC, Australia, 3086.
authors.forename: O
authors.initials: O
authors.lastname: Sanislav
authors.affiliation: Department of Microbiology, La Trobe University, Plenty Rd., Bundoora, VIC, Australia, 3086.
authors.forename: A J
authors.initials: AJ
authors.lastname: Chavan
authors.affiliation: Department of Microbiology, La Trobe University, Plenty Rd., Bundoora, VIC, Australia, 3086.
authors.forename: C
authors.initials: C
authors.lastname: Farah
authors.affiliation: Department of Microbiology, La Trobe University, Plenty Rd., Bundoora, VIC, Australia, 3086.
authors.forename: S W
authors.initials: SW
authors.lastname: De Piazza
authors.affiliation: Department of Microbiology, La Trobe University, Plenty Rd., Bundoora, VIC, Australia, 3086.
authors.forename: C L
authors.initials: CL
authors.lastname: Storey
authors.affiliation: Department of Microbiology, La Trobe University, Plenty Rd., Bundoora, VIC, Australia, 3086.
authors.forename: J
authors.initials: J
authors.lastname: Ilievska
authors.affiliation: Department of Microbiology, La Trobe University, Plenty Rd., Bundoora, VIC, Australia, 3086.
authors.forename: S G
authors.initials: SG
authors.lastname: Fernando
authors.affiliation: Department of Microbiology, La Trobe University, Plenty Rd., Bundoora, VIC, Australia, 3086.
authors.forename: P K
authors.initials: PK
authors.lastname: Smith
authors.affiliation: Department of Microbiology, La Trobe University, Plenty Rd., Bundoora, VIC, Australia, 3086.
authors.forename: S T
authors.initials: ST
authors.lastname: Lay
authors.affiliation: Department of Microbiology, La Trobe University, Plenty Rd., Bundoora, VIC, Australia, 3086. Electronic address: P.Fisher@latrobe.edu.au.
authors.forename: P R
authors.initials: PR
authors.lastname: Fisher
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D001928:Brain Diseases, Metabolic / Q000378:metabolism / Q000473:pathology; D004023:Dictyostelium / Q000235:genetics / Q000378:metabolism / Q000648:ultrastructure; D006801:Humans; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D028361:Mitochondrial Diseases / Q000378:metabolism / Q000473:pathology; D008959:Models, Neurological; D030781:Organisms, Genetically Modified; D010085:Oxidative Phosphorylation
chemical_list: D055372:AMP-Activated Protein Kinases
keywords: AMPK; Dictyostelium; Lysosomal disease; Mitochondrial disease; OXPHOS; neurodegenerative disease