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Will Probing Flies and Worms Bear Fruit in the Search for New Genes Involved in Alzheimer's?
Mel Feany led this live discussion on 29 October 2002. Readers are invited to submit additional comments by using our Comments form at the bottom of the page.
 View Transcript of Live Discussion — Posted 28 August 2006
Background Text
By Mel B. Feany
The progressive loss of specific neuronal populations is what is thought to cause the major symptoms and early death seen in human neurodegenerative diseases. The identification of causative single gene mutations in families with inherited forms of these disorders has facilitated modeling of these diseases in experimental organisms, including the fruit fly Drosophila melanogaster and the roundworm Caenorhabditis elegans.
Many neurodegenerative diseases have now been modeled in Drosophila and C. elegans, including Alzheimer's, Parkinson's, Huntington's, human tauopathies, and several of the spinocerebellar ataxias. In our lab, we have introduced normal and mutated human tau into fruit flies, which then develop progressive neurodegeneration (see news). We have also found normal and mutant forms of human α-synuclein induce degeneration of dopaminergic neurons (see news). Second-site genetic analysis, i.e. looking for additional sites that enhance or suppress the primary phenotype, is currently ongoing for many of these models. Our group has identified numerous modifier genes, some expected, some novel, which we are now analyzing. This is where the strength of Drosophila genetics becomes apparent, as genetic-modifier screens yield results faster and more cheaply than in vertebrate models. Fruit fly modifiers can then be checked for mammalian homologues. In this way, fly genetics represents one strategy to try to identify genes involved in Alzheimer's that are now implicated by linkage peak analysis only. The table (to be posted) summarizes the main features of the currently available fly and worm models.
The approach relies on the assumptions that fruit fly genetics can indeed define the molecular pathways underlying human neurodegenerative processes and that it provides new therapeutic targets and drug screens.
Despite extensive research in vertebrate systems, many questions regarding the pathogenesis of neurodegenerative diseases still remain. What are the cellular pathways mediating neurodegeneration? What underlies the remarkable tissue and cellular specificity seen in these diseases? What is the role of inclusion bodies?
In our discussion it may be useful to consider the role that Drosophila and C. elegans models have in addressing these key questions.
- What are the strengths of the models?
- What features of the human diseases should simple models recapitulate?
- What are the limitations of the models? For example, the extensive anatomic differences between the fly and vertebrate motor systems might limit this model's contribution to answering questions about how loss of specific populations of dopamine neurons causes the abnormal movements in Parkinson's disease. Are there other differences between vertebrates and invertebrates that will restrict the utility of fly models of neurodegenerative disease?
- What other questions could be addressed with these models? AβPP processing and the downstream fate of AβPP's cleavage products, or intracellular actions and binding partners of Aβ come to mind.
Editor's Recommended References:
Link CD. Expression of human beta-amyloid peptide in transgenic Caenorhabditis elegans. Proc Natl Acad Sci U S A. 1995 Sep 26;92(20):9368-72. Abstract
Fonte V, Kapulkin V, Taft A, Fluet A, Friedman D, Link CD. Interaction of intracellular beta amyloid peptide with chaperone proteins. Proc Natl Acad Sci U S A 2002 Jul 9;99(14):9439-44.
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Faber PW, Alter JR, MacDonald ME, Hart AC. Polyglutamine-mediated dysfunction and apoptotic death of a Caenorhabditis elegans sensory neuron. Proc Natl Acad Sci U S A. 1999 Jan 5;96(1):179-84.
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Jackson GR, Wiedau-Pazos M, Sang TK, Wagle N, Brown CA, Massachi S, Geschwind DH. Human wild-type tau interacts with wingless pathway components and produces neurofibrillary pathology in Drosophila. Neuron 2002 May 16;34(4):509-19.
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Muqit MM, Feany MB. Modeling neurodegenerative diseases in Drosophila: a fruitful approach?
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Link CD. Transgenic invertebrate models of age-associated neurodegenerative diseases. Mech Ageing Dev 2001 Sep 30;122(14):1639-49.
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Chan HY, Bonini NM. Drosophila models of human neurodegenerative disease. Cell Death Differ 2000 Nov;7(11):1075-80.
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Further Reading About Flies' and Worms' Contributions to AD Gene Discovery:
Tickoo S, Russell S. Drosophila melanogaster as a model system for drug discovery and pathway screening. Curr Opin Pharmacol 2002 Oct;2(5):555. Abstract
Li J, Pauley AM, Myers RL, Shuang R, Brashler JR, Yan R, Buhl AE, Ruble C, Gurney ME. SEL-10 interacts with presenilin 1, facilitates its ubiquitination, and alters A-beta peptide production. J Neurochem 2002 Sep;82(6):1540-8. Abstract
Zambrano N, Bimonte M, Arbucci S, Gianni D, Russo T, Bazzicalupo P. feh-1 and apl-1, the Caenorhabditis elegans orthologues of mammalian Fe65 and beta-amyloid precursor protein genes, are involved in the same pathway that controls nematode pharyngeal pumping. J Cell Sci 2002 Apr 1;115(Pt 7):1411-22. Abstract
Gunawardena S, Goldstein LS. Disruption of axonal transport and neuronal viability by amyloid precursor protein mutations in Drosophila. Neuron 2001 Nov 8;32(3):389-401. (Related news)
Chung HM, Struhl G. Nicastrin is required for Presenilin-mediated transmembrane cleavage in Drosophila. Nat Cell Biol 2001 Dec;3(12):1129-32. Abstract
Zhang SX, Guo Y, Boulianne GL. Identification of a novel family of putative methyltransferases that interact with human and Drosophila presenilins. Zhang SX, Guo Y, Boulianne GL. Gene 2001 Dec 12;280(1-2):135-44. Abstract
Anderton BH. Alzheimer's disease: clues from flies and worms. Curr Biol 1999 Feb 11;9(3):R106-9.
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