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  • Review Article
  • Published:

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

Nature Reviews Genetics volume 10, pages 359–370 (2009)Cite this article

Key Points

  • More than 40 Drosophila melanogaster genes have been discovered for which recessive, loss-of-function mutations cause adult onset degeneration of the central nervous system (CNS). A table presenting these genes is provided, and an expanded, updated version can be found at the Bonini laboratory homepage.

  • Almost all of these genes have easily identifiable orthologues in the mouse and human. Over half have mouse or human orthologues that are also associated with neurodegeneration.

  • The swiss cheese (sws) gene demonstrates the value of unbiased screens in the fly. Since its discovery, two biochemical functions have been characterized for the protein; loss of the mouse orthologue in the brain has been shown to cause neurodegeneration, and loss-of-function mutations in the human orthologue have been discovered as the cause of spastic paraplegia 39.

  • Pink1 and park are associated with Parkinson's disease, and they demonstrate the value of epistasis experiments in the fly, which have shown that these two genes function together in a pathway that regulates mitochondrial fusion and fission.

  • Fly neurodegeneration genes can be grouped into the following cellular processes: mitochondrial function, signal transduction, lipid homeostasis, protein homeostasis and the cytoskeleton. Many of the genes have roles in more than one of these processes.

  • Some glial-specific genes have been shown to be required for maintaining neurons in the adult. Mutations in other, more widely expressed genes have defective glia, underscoring the importance of glia in CNS integrity.

  • Many genetic tricks are possible in the fly, such as: the precise control in space and time of the expression of transgenes, including through RNAi constructs; and the possibility of making marked homozygous mutant clones as small as a single neuron in otherwise heterozygous animals. These techniques, and the ease of forward genetics screens for identifying new neurodegeneration mutants, ensure that D. melanogaster will remain a key tool for the analysis of genes required for CNS integrity.

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.

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Figure 1: Cellular processes implicated by neurodegeneration genes.
Figure 2: Neurodegeneration proteins associated with the mitochondrion.

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Acknowledgements

We thank M. Bland, N. Liu, Z. Yu, L.-Y. Hao and C.J. Thut for comments on the manuscript. N.M.B receives funding from the National Institute of Aging and the National Institute of Neurological Disorders and Stroke, and she is an Investigator of the Howard Hughes Medical Institute.

Author information

Authors and Affiliations

  1. Howard Hughes Medical Institute, 306 Leidy Laboratoriess, 433 South University Avenue, Philadelphia, 19104, Pennsylvania, USA

    Derek Lessing & Nancy M. Bonini

  2. Department of Biology, University of Pennsylvania, 306 Leidy Laboratoriess, 433 South University Avenue, Philadelphia, 19104, Pennsylvania, USA

    Nancy M. Bonini

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  1. Derek Lessing
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Correspondence to Nancy M. Bonini.

Supplementary information

Supplementary Table 1

Neurodegeneration Due to Loss-of-Function Mutations. (PDF 335 kb)

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DATABASES

Flybase

dare

drd

Eaat1

park

Pink1

sws

OMIM

adrenoleukodystrophy

Alzheimer's disease

Charcot–Marie–Tooth type 2A

juvenile onset parkinsonism

Niemann–Pick disease

Parkinson's disease

progressive external opthalmoplegia 2

FURTHER INFORMATION

Bonini Laboratory

Flybrain

Homophila

Mouse Genome Informatics

Glossary

RNAi

RNAi in the adult fly is achieved with transgenic constructs expressing an inverted repeat sequence targeted to the mRNA of interest. The expressed dsRNA is processed in vivo into short interfering RNAs, which lead to degradation of the target gene transcripts for a loss-of-function mutant effect.

Mosaic

An animal comprised of tissue of different genotypes. In flies, mosaics are generated by site-specific recombination, to yield homozygous mutant tissue or cells in an otherwise heterozygous animal.

Glia

Support cells for neurons.

Phototaxis

Movement towards a light source. A behaviour often used in flies to test locomotor activity and eye function.

Parkinsonism

Showing symptoms characteristic of Parkinsons disease (tremor, rigidity, slowing of movement, postural instability and shuffling gait) that respond to treatment with dopamine.

Purkinje cells

Vertebrate neurons with huge, dense dendrites that integrate complex inputs in the cerebellum and project axons to the deep motor nuclei of the brain.

Ubiquitin-proteasome system

Members of a large family of E3 ubiquitin ligases recognize specific substrate proteins, tagging them by polyubiquitination for degradation in the proteasome, a large cylindrical protein complex.

Autophagy

More precisely, macroautophagy — the engulfment of protein aggregates or organelles by vesicles with double-bilayer membranes, which then fuse with lysosomes for degradation of their contents.

Neurite

General term for axons and dendrites.

Amyloid

Protein aggregates that accumulate as fibres of 7–10 nm in diameter with common structural features including β-pleated sheet conformation and resistance to detergents and proteases.

Ecdysteroids

Steroids that are similar in structure to ecdysones, found in arthropods and some plants.

Ecdysone

Steroid hormone found in arthropods. In insects, 20-hydroxyecdysone stimulates moulting and metamorphosis.

Excitotoxicity

The over-stimulation of excitatory neurotransmitter receptors, which causes an influx of calcium in the postsynaptic neuron.

Haemolymph

The interstitial fluid in insects, which have an open circulatory system. Unlike blood, haemolymph has only a small role in carrying O2 and CO2, which is principally done by the tracheal system.

Optic lobes

Large, bilaterally symmetric structures of the fly brain that process visual input.

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Lessing, D., Bonini, N. Maintaining the brain: insight into human neurodegeneration from Drosophila melanogaster mutants. Nat Rev Genet 10, 359–370 (2009). https://doi.org/10.1038/nrg2563

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