Home LiteratureArticle Details
PMID: 19434080 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Review

Maintaining the brain: insight into human neurodegeneration from Drosophila melanogaster mutants.

Nature reviews. Genetics ·Vol. 10 ·No. 6 ·2009-06-00 ·Pages 359-70

Lessing D, Bonini NM

Abstract

The fruitfly Drosophila melanogaster has enabled significant advances in neurodegenerative disease research, notably in the identification of genes that are required to maintain the structural integrity of the brain, defined by recessive mutations that cause adult onset neurodegeneration. Here, we survey these genes in the fly and classify them according to five key cell biological processes. Over half of these genes have counterparts in mice or humans that are also associated with neurodegeneration. Fly genetics continues to be instrumental in the analysis of degenerative disease, with notable recent advances in our understanding of several inherited disorders, Parkinson's disease, and the central role of mitochondria in neuronal maintenance.

MeSH Terms
Animals Animals, Genetically Modified Brain/physiology Drosophila Proteins/genetics Drosophila melanogaster/genetics Humans Mutation/genetics Nerve Degeneration Neurodegenerative Diseases/genetics,therapy
Chemicals
Drosophila Proteins
Authors & Affiliations
2 authors, click to expand affiliations / ORCID
Lessing Derek
Howard Hughes Medical Institute, University of Pennsylvania, 306 Leidy Laboratories, 433 South University Avenue, Philadelphia, Pennsylvania 19104, USA.
Bonini Nancy M
References (97)
97 references, click to expand
  1. Molecular analysis of sleep: wake cycles in Drosophila.
    Cold Spring Harb Symp Quant Biol. 2007;72:557-64 PMID: 18419315
  2. Techniques to dissect cellular and subcellular function in the Drosophila nervous system.
    Methods Cell Biol. 2003;71:195-265 PMID: 12884693
  3. Spatiotemporal gene expression targeting with the TARGET and gene-switch systems in Drosophila.
    Sci STKE. 2004 Feb 12;2004(220):pl6 PMID: 14970377
  4. Cholesterol homeostasis and function in neurons of the central nervous system.
    Cell Mol Life Sci. 2003 Jun;60(6):1158-71 PMID: 12861382
  5. Defective glia induce neuronal apoptosis in the repo visual system of Drosophila.
    Neuron. 1995 Mar;14(3):581-90 PMID: 7695904
  6. Degeneration of neural cells in the central nervous system of mice deficient in the gene for the adhesion molecule on Glia, the beta 2 subunit of murine Na,K-ATPase.
    J Cell Biol. 1994 Nov;127(3):835-45 PMID: 7525597
  7. Mosaic analysis with a repressible cell marker for studies of gene function in neuronal morphogenesis.
    Neuron. 1999 Mar;22(3):451-61 PMID: 10197526
  8. Paralysis and early death in cysteine string protein mutants of Drosophila.
    Science. 1994 Feb 18;263(5149):977-80 PMID: 8310297
  9. Drosophila Omi, a mitochondrial-localized IAP antagonist and proapoptotic serine protease.
    EMBO J. 2007 Jul 11;26(13):3144-56 PMID: 17557079
  10. Genetic and genomic studies of Drosophila parkin mutants implicate oxidative stress and innate immune responses in pathogenesis.
    Hum Mol Genet. 2005 Mar 15;14(6):799-811 PMID: 15689351
  11. The Parkinson's disease genes pink1 and parkin promote mitochondrial fission and/or inhibit fusion in Drosophila.
    Proc Natl Acad Sci U S A. 2008 Sep 23;105(38):14503-8 PMID: 18799731
  12. Homophila: human disease gene cognates in Drosophila.
    Nucleic Acids Res. 2002 Jan 1;30(1):149-51 PMID: 11752278
  13. Mitochondrial pathology and muscle and dopaminergic neuron degeneration caused by inactivation of Drosophila Pink1 is rescued by Parkin.
    Proc Natl Acad Sci U S A. 2006 Jul 11;103(28):10793-8 PMID: 16818890
  14. Evolution of mitochondrial cell death pathway: Proapoptotic role of HtrA2/Omi in Drosophila.
    Biochem Biophys Res Commun. 2007 May 18;356(4):993-7 PMID: 17397804
  15. Alpha-synuclein cooperates with CSPalpha in preventing neurodegeneration.
    Cell. 2005 Nov 4;123(3):383-96 PMID: 16269331
  16. The Drosophila easily shocked gene: a mutation in a phospholipid synthetic pathway causes seizure, neuronal failure, and paralysis.
    Cell. 1994 Oct 7;79(1):23-33 PMID: 7923374
  17. Unrestricted synaptic growth in spinster-a late endosomal protein implicated in TGF-beta-mediated synaptic growth regulation.
    Neuron. 2002 Oct 24;36(3):403-16 PMID: 12408844
  18. Metabolic disruption in Drosophila bang-sensitive seizure mutants.
    Genetics. 2006 Jul;173(3):1357-64 PMID: 16648587
  19. AMP-activated protein kinase in metabolic control and insulin signaling.
    Circ Res. 2007 Feb 16;100(3):328-41 PMID: 17307971
  20. PINK1 protects against oxidative stress by phosphorylating mitochondrial chaperone TRAP1.
    PLoS Biol. 2007 Jul;5(7):e172 PMID: 17579517
  21. Normal mitochondrial dynamics requires rhomboid-7 and affects Drosophila lifespan and neuronal function.
    Curr Biol. 2006 May 23;16(10):982-9 PMID: 16713954
  22. Mapping of behaviour in Drosophila mosaics.
    Nature. 1972 Dec 29;240(5383):527-35 PMID: 4568399
  23. Disruption of the MAP1B-related protein FUTSCH leads to changes in the neuronal cytoskeleton, axonal transport defects, and progressive neurodegeneration in Drosophila.
    Mol Biol Cell. 2005 May;16(5):2433-42 PMID: 15772149
  24. Mutations in cytochrome c oxidase subunit VIa cause neurodegeneration and motor dysfunction in Drosophila.
    Genetics. 2007 Jun;176(2):937-46 PMID: 17435251
  25. Localized effects of cAMP mediated by distinct routes of protein kinase A.
    Physiol Rev. 2004 Jan;84(1):137-67 PMID: 14715913
  26. Neuropathy target esterase and a homologous Drosophila neurodegeneration-associated mutant protein contain a novel domain conserved from bacteria to man.
    Biochem J. 1998 May 15;332 ( Pt 1):1-4 PMID: 9576844
  27. Autophagy in the pathogenesis of disease.
    Cell. 2008 Jan 11;132(1):27-42 PMID: 18191218
  28. Behavioral and biochemical defects in temperature-sensitive acetylcholinesterase mutants of Drosophila melanogaster.
    Genetics. 1980 Dec;96(4):939-65 PMID: 6790339
  29. Swiss Cheese, a protein involved in progressive neurodegeneration, acts as a noncanonical regulatory subunit for PKA-C3.
    J Neurosci. 2008 Oct 22;28(43):10885-92 PMID: 18945896
  30. Cholesterol in Alzheimer's disease.
    Lancet Neurol. 2005 Dec;4(12):841-52 PMID: 16297842
  31. The evolution of signalling pathways in animal development.
    Nat Rev Genet. 2003 Jan;4(1):39-49 PMID: 12509752
  32. Greased hedgehogs: new links between hedgehog signaling and cholesterol metabolism.
    Bioessays. 2007 Nov;29(11):1085-94 PMID: 17935218
  33. The PINK1/Parkin pathway regulates mitochondrial morphology.
    Proc Natl Acad Sci U S A. 2008 Feb 5;105(5):1638-43 PMID: 18230723
  34. Niemann-Pick type C disease involves disrupted neurosteroidogenesis and responds to allopregnanolone.
    Nat Med. 2004 Jul;10(7):704-11 PMID: 15208706
  35. A genetic method for generating Drosophila eyes composed exclusively of mitotic clones of a single genotype.
    Genetics. 1999 Aug;152(4):1631-9 PMID: 10430588
  36. Mitochondrial fusion protects against neurodegeneration in the cerebellum.
    Cell. 2007 Aug 10;130(3):548-62 PMID: 17693261
  37. Mitochondrial encephalomyopathy in Drosophila.
    J Neurosci. 2006 Jan 18;26(3):810-20 PMID: 16421301
  38. The role of chaperones in polyglutamine disease.
    Trends Mol Med. 2002 May;8(5):232-6 PMID: 12067633
  39. A mitochondrial paradigm of metabolic and degenerative diseases, aging, and cancer: a dawn for evolutionary medicine.
    Annu Rev Genet. 2005;39:359-407 PMID: 16285865
  40. Regulation of armadillo by a Drosophila APC inhibits neuronal apoptosis during retinal development.
    Cell. 1998 Jun 26;93(7):1171-82 PMID: 9657150
  41. A functional misexpression screen uncovers a role for enabled in progressive neurodegeneration.
    PLoS One. 2008 Oct 08;3(10):e3332 PMID: 18841196
  42. Reactive oxygen species act remotely to cause synapse loss in a Drosophila model of developmental mitochondrial encephalopathy.
    Development. 2008 Aug;135(15):2669-79 PMID: 18599508
  43. Parkinson's disease.
    Hum Mol Genet. 2007 Oct 15;16 Spec No. 2:R183-94 PMID: 17911161
  44. A-to-I pre-mRNA editing in Drosophila is primarily involved in adult nervous system function and integrity.
    Cell. 2000 Aug 18;102(4):437-49 PMID: 10966106
  45. Molecular biology and anatomy of Drosophila olfactory associative learning.
    Bioessays. 2001 Jul;23(7):571-81 PMID: 11462211
  46. The mitochondrial serine protease HtrA2/Omi: an overview.
    Cell Death Differ. 2008 Mar;15(3):453-60 PMID: 18174901
  47. Drosophila NMNAT maintains neural integrity independent of its NAD synthesis activity.
    PLoS Biol. 2006 Nov;4(12):e416 PMID: 17132048
  48. Defective glia in the Drosophila brain degeneration mutant drop-dead.
    Neuron. 1993 May;10(5):839-50 PMID: 8494644
  49. Decreasing glutamate buffering capacity triggers oxidative stress and neuropil degeneration in the Drosophila brain.
    Curr Biol. 2004 Apr 6;14(7):599-605 PMID: 15062101
  50. Neural dysfunction and neurodegeneration in Drosophila Na+/K+ ATPase alpha subunit mutants.
    J Neurosci. 2003 Feb 15;23(4):1276-86 PMID: 12598616
  51. Motor discoordination and increased susceptibility to cerebellar injury in GLAST mutant mice.
    Eur J Neurosci. 1998 Mar;10(3):976-88 PMID: 9753165
  52. The swiss cheese mutant causes glial hyperwrapping and brain degeneration in Drosophila.
    J Neurosci. 1997 Oct 1;17(19):7425-32 PMID: 9295388
  53. PINK1 controls mitochondrial localization of Parkin through direct phosphorylation.
    Biochem Biophys Res Commun. 2008 Dec 19;377(3):975-80 PMID: 18957282
  54. PINK1-associated Parkinson's disease is caused by neuronal vulnerability to calcium-induced cell death.
    Mol Cell. 2009 Mar 13;33(5):627-38 PMID: 19285945
  55. Signaling receptome: a genomic and evolutionary perspective of plasma membrane receptors involved in signal transduction.
    Sci STKE. 2003 Jun 17;2003(187):RE9 PMID: 12815191
  56. Drosophila pink1 is required for mitochondrial function and interacts genetically with parkin.
    Nature. 2006 Jun 29;441(7097):1162-6 PMID: 16672981
  57. Axonal regeneration in adult CNS neurons--signaling molecules and pathways.
    J Neurochem. 2006 Mar;96(6):1501-8 PMID: 16476081
  58. Parkin is recruited selectively to impaired mitochondria and promotes their autophagy.
    J Cell Biol. 2008 Dec 1;183(5):795-803 PMID: 19029340
  59. Fly fighting: octopamine modulates aggression.
    Curr Biol. 2008 Feb 26;18(4):R161-3 PMID: 18302917
  60. Mitochondrial dysfunction in Drosophila PINK1 mutants is complemented by parkin.
    Nature. 2006 Jun 29;441(7097):1157-61 PMID: 16672980
  61. Neuropathology in Drosophila mutants with increased seizure susceptibility.
    Genetics. 2008 Feb;178(2):947-56 PMID: 18245348
  62. Glial cell biology in Drosophila and vertebrates.
    Trends Neurosci. 2006 Feb;29(2):82-90 PMID: 16377000
  63. Tools for neuroanatomy and neurogenetics in Drosophila.
    Proc Natl Acad Sci U S A. 2008 Jul 15;105(28):9715-20 PMID: 18621688
  64. Neuronal loss of Drosophila NPC1a causes cholesterol aggregation and age-progressive neurodegeneration.
    J Neurosci. 2008 Jun 25;28(26):6569-82 PMID: 18579730
  65. Loss-of-function of human PINK1 results in mitochondrial pathology and can be rescued by parkin.
    J Neurosci. 2007 Nov 7;27(45):12413-8 PMID: 17989306
  66. A tribute to Seymour Benzer, 1921--2007.
    Genetics. 2008 Nov;180(3):1265-73 PMID: 19001297
  67. Acetylcholinesterase mutants in Drosophila and their effects on the structure and function of the central nervous system.
    J Comp Neurol. 1980 Feb 15;189(4):741-74 PMID: 6769980
  68. Presynaptic dysfunction in Drosophila csp mutants.
    Neuron. 1994 Oct;13(4):899-907 PMID: 7946336
  69. Phosphatidylserine and phosphatidylethanolamine in mammalian cells: two metabolically related aminophospholipids.
    J Lipid Res. 2008 Jul;49(7):1377-87 PMID: 18204094
  70. Carnitine-acylcarnitine translocase deficiency, clinical, biochemical and genetic aspects.
    Mol Aspects Med. 2004 Oct-Dec;25(5-6):521-32 PMID: 15363639
  71. Mutations in String/CDC25 inhibit cell cycle re-entry and neurodegeneration in a Drosophila model of Ataxia telangiectasia.
    Genes Dev. 2008 May 1;22(9):1205-20 PMID: 18408079
  72. The synaptic vesicle protein CSP alpha prevents presynaptic degeneration.
    Neuron. 2004 Apr 22;42(2):237-51 PMID: 15091340
  73. Role of adenine nucleotide translocator 1 in mtDNA maintenance.
    Science. 2000 Aug 4;289(5480):782-5 PMID: 10926541
  74. Mitochondrial pathology and apoptotic muscle degeneration in Drosophila parkin mutants.
    Proc Natl Acad Sci U S A. 2003 Apr 1;100(7):4078-83 PMID: 12642658
  75. Phosphoinositides in cell regulation and membrane dynamics.
    Nature. 2006 Oct 12;443(7112):651-7 PMID: 17035995
  76. Apoptosis in neurodegenerative disorders.
    Nat Rev Mol Cell Biol. 2000 Nov;1(2):120-9 PMID: 11253364
  77. Mechanisms of Parkinson's disease linked to pathological alpha-synuclein: new targets for drug discovery.
    Neuron. 2006 Oct 5;52(1):33-8 PMID: 17015225
  78. Down-regulation of torp4a, encoding the Drosophila homologue of torsinA, results in increased neuronal degeneration.
    J Neurobiol. 2006 Oct;66(12):1338-53 PMID: 16967506
  79. Drosophila alicorn is a neuronal maintenance factor protecting against activity-induced retinal degeneration.
    J Neurosci. 2008 Jun 18;28(25):6419-29 PMID: 18562613
  80. Neuronal glutathione deficiency and age-dependent neurodegeneration in the EAAC1 deficient mouse.
    Nat Neurosci. 2006 Jan;9(1):119-26 PMID: 16311588
  81. Aberrant lysosomal carbohydrate storage accompanies endocytic defects and neurodegeneration in Drosophila benchwarmer.
    J Cell Biol. 2005 Jul 4;170(1):127-39 PMID: 15998804
  82. The neurodegeneration mutant löchrig interferes with cholesterol homeostasis and Appl processing.
    EMBO J. 2002 Dec 2;21(23):6367-76 PMID: 12456644
  83. De novo CoA biosynthesis is required to maintain DNA integrity during development of the Drosophila nervous system.
    Hum Mol Genet. 2008 Jul 1;17(13):2058-69 PMID: 18407920
  84. Phototransduction and retinal degeneration in Drosophila.
    Pflugers Arch. 2007 Aug;454(5):821-47 PMID: 17487503
  85. Neuropathy target esterase and phospholipid deacylation.
    Biochim Biophys Acta. 2005 Sep 15;1736(2):87-93 PMID: 16137924
  86. Proteasome-independent functions of ubiquitin in endocytosis and signaling.
    Science. 2007 Jan 12;315(5809):201-5 PMID: 17218518
  87. Preventing neurodegeneration in the Drosophila mutant bubblegum.
    Science. 1999 Jun 18;284(5422):1985-8 PMID: 10373116
  88. Conserved genetic programs in insect and mammalian brain development.
    Bioessays. 1999 Aug;21(8):677-84 PMID: 10440864
  89. The dare gene: steroid hormone production, olfactory behavior, and neural degeneration in Drosophila.
    Development. 1999 Oct;126(20):4591-602 PMID: 10498693
  90. Subunit-destabilizing mutations in Drosophila copper/zinc superoxide dismutase: neuropathology and a model of dimer dysequilibrium.
    Proc Natl Acad Sci U S A. 1995 Sep 12;92(19):8574-8 PMID: 7567977
  91. Brain-specific deletion of neuropathy target esterase/swisscheese results in neurodegeneration.
    Proc Natl Acad Sci U S A. 2004 Apr 6;101(14):5075-80 PMID: 15051870
  92. Neuropathy target esterase gene mutations cause motor neuron disease.
    Am J Hum Genet. 2008 Mar;82(3):780-5 PMID: 18313024
  93. Spongecake and eggroll: two hereditary diseases in Drosophila resemble patterns of human brain degeneration.
    Curr Biol. 1997 Nov 1;7(11):885-8 PMID: 9382801
  94. Parkin: a multifaceted ubiquitin ligase.
    Biochem Soc Trans. 2006 Nov;34(Pt 5):749-53 PMID: 17052189
  95. The mitochondrial protease HtrA2 is regulated by Parkinson's disease-associated kinase PINK1.
    Nat Cell Biol. 2007 Nov;9(11):1243-52 PMID: 17906618
  96. Temperature-sensitive paralytic mutants are enriched for those causing neurodegeneration in Drosophila.
    Genetics. 2002 Jul;161(3):1197-208 PMID: 12136022
  97. Loss of Swiss cheese/neuropathy target esterase activity causes disruption of phosphatidylcholine homeostasis and neuronal and glial death in adult Drosophila.
    J Neurosci. 2005 Mar 16;25(11):2865-73 PMID: 15772346
Article Info
Journal
Nature reviews. Genetics
Abbr.
Nat Rev Genet
ISSN
1471-0064
DOI
10.1038/nrg2563
Published
2009-06-00
Pages
359-70
Language
English
Region
England
NLM ID
100962779
PMCID
PMC2820605
Subset
IM
Grants
NIA NIH HHS · P01 AG009215-190008 · United States
NIA NIH HHS · P01 AG009215 · United States
NIA NIH HHS · P01 AG009215-180008 · United States
Howard Hughes Medical Institute · United States
NINDS NIH HHS · R01 NS043578 · United States
NINDS NIH HHS · R01 NS043578-05 · United States
External Links
PubMed source DOI: 10.1038/nrg2563 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2