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  • Review Article
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Dying for a cause: invertebrate genetics takes on human neurodegeneration

Nature Reviews Genetics volume 4, pages 181–194 (2003)Cite this article

Key Points

  • The mechanisms of neuronal cell death that accompany injury and neurodegenerative disease are conserved from invertebrates to humans and, therefore, the molecular genetic dissection of these mechanisms in nematodes and flies can provide new insights into neurodegeneration.

  • Hypoxia activates a conserved response in which the oxygen sensor EGL-9 indirectly regulates the stability of the transcription factor HIFα. Invertebrate genetics have implicated ADAR RNA-editing function and part of an insulin-like signalling pathway (DAF-2 insulin like receptor, DAF-18/PTEN and DAF-16 forkhead transcription factor) in hypoxia sensitivity.

  • Ion-channel hyperactivation in nematodes and flies can induce necrotic cell-death in a similar way to mammalian excitotoxicity. Dissection of the mechanisms of necrosis in nematodes confirms that under conditions of excess ion influx, intracellular calcium levels rise and calpain and cathepsin proteases are activated.

  • A subset of nematode and fly models of neurodegenerative disorders involve homologues of human disease genes — for example, worm cup-5 and human mucolipidosis type IV, and fly Crumbs and human retinitis pigmentosa — or seem to affect common pathways (such as fly bubblegum and human adrenoleukodystrophy).

  • The over-expression of human disease genes in nematodes and flies has been highly successful in modelling human neurodegenerative disorders, including the pathology of Aβ1-42 (implicated in Alzheimer disease), α-synuclein (implicated in Parkinson disease), and expanded polygultamine tract proteins (implicated in several disorders including Huntington disease).

  • Processing of the human amyloid precursor protein (APP) and the Notch family of transmembrane receptors is accomplished by presenilins, which can cause human Alzheimer disease when mutated. Invertebrate genetics has helped to identify several proteins (for example, APH-2/agoraphobic/nicastrin, and APH-1, PEN-1 and SEL-10) that interact with presenilins to influence potentially toxic cleavage functions.

  • The over-expression of human α-synuclein in flies can induce relatively selective degeneration of dopaminergic neurons that include structures that resemble Lewy bodies — characteristic of human Parkinson disease. The overexpression of heat-shock chaperones HSP70 and/or HSP40, or treatment with geldanamycin (which enhances HSP70 activity) can be neuroprotective in this model.

  • The over-expression of proteins or fragments that include 'expanded' polyglutamine tracts induces neurodegeneration, which occurs in human Huntington disease, spinobulbar muscular atrophy and the spinocerebellar ataxias. Genetic suppressor screens in flies have implicated HSP70 and HSP40 as neuroprotective. Moreover, such screens have identified new death-suppressors that might be exploited for the design of therapeutics.

  • An unanticipated theme emerging from several distinct models of neurodegenerative disorders (Alzheimer disease, Parkinson disease and polyglutamine-expansion disorders) is that an increase in the activities of specific heat-shock proteins is neuroprotective. Therefore, disrupted protein folding/turnover might lie at the heart of several neurodegenerative conditions.

Abstract

If invertebrate neurons are injured by hostile environments or aberrant proteins they die much like human neurons, indicating that the powerful advantages of invertebrate molecular genetics might be successfully used for testing specific hypotheses about human neurological diseases, for drug discovery and for non-biased screens for suppressors and enhancers of neurodegeneration. Recent molecular dissection of the genetic requirements for hypoxia, excitotoxicity and death in models of Alzheimer disease, polyglutamine-expansion disorders, Parkinson disease and more, is providing mechanistic insights into neurotoxicity and suggesting new therapeutic interventions. An emerging theme is that neuronal crises of distinct origins might converge to disrupt common cellular functions, such as protein folding and turnover.

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Figure 1: A working model of excitotoxic-like ion-channel-induced neurodegeneration in Caenorhabditis elegans.
Figure 2: HSP70 suppresses degeneration of the fly eye caused by polyglutamine expression.

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Acknowledgements

We thank I. Mano and G. Stamatas for critical reading of the manuscript. B.G. is a Fullbright grantee and was supported by a Louis Bevier Graduate Fellowship. Work was supported in part by grants from the National Institutes of Health/National Institute of Neurological Disorders and Stroke, and the National Institute on Ageing.

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Authors and Affiliations

  1. Department of Molecular Biology and Biochemistry, Rutgers, The State University of New Jersey, A232 Nelson Biological Laboratories, 604 Allison Road, Piscataway, 08855, New Jersey, USA

    Monica Driscoll & Beate Gerstbrein

Authors
  1. Monica Driscoll
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  2. Beate Gerstbrein
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Correspondence to Monica Driscoll.

Supplementary information

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DATABASES

LocusLink

apl-1

Appl

bubblegum

Cacophony

cup-5

daf-2

DAF-16

DAF-18

drop-dead

eggroll

egl-9

HSPA1L

lin-12

mec-4

MJD

sel-10

sel-12

spinster

spongecake

swiss cheese

vacuous

OMIM

adrenoleukodystrophy

Alzheimer disease

Autosomal recessive juvenile-onset parkinsonism

Creutzfeldt–Jakob disease

dentatorubral pallidoluysian atrophy

Gerstmann–Straussler disease

human mucolipidosis type IV

Huntington disease

kuru

Leber's congenital amaurosis

neural ceroid lipofuscinoses

Niemann–Pick disease

Parkinson disease

retinitis pigmentosa

SCA1

SCA2

SCA3

SCA6

SCA7

SCA17

spinobulbar muscular atrophy

Tay–Sachs disease

Swiss-Prot

ADAR

APP

CA150

DAF-2

EGL-9

HIF-1α

ITR-1

WormBase

UNC-68

Glossary

RNA INTERFERENCE

(RNAi). A form of post-transcriptional gene silencing, in which double-stranded RNA induces degradation of the homologous endogenous transcripts, mimicking the effect of the reduction, or loss, of gene activity.

UBIQUITYLATION

A regulated process by which ubiquitin residues are conjugated to influence transport (mono-ubiquitylation) or to mark proteins for degradation (poly-ubiquitylation).

PROTEASOME

A cytosolic protein complex that degrades proteins that have been marked for destruction by the ubiquitylation pathway.

DAUER

An alternative developmental larval stage that worms enter when food is lacking, the population is crowded or growth temperatures are suboptimal.

DESENSITIZATION

Adaptive changes in ion-channel signalling that limit the responses to continuous receptor stimulation.

MULTILAMELLAR INCLUSIONS

Electron-dense lipid-containing subcellular structures — which often appear as concentric layers — that are observed in lipid-storage diseases and other neurodegenerative conditions.

ISCHAEMIA

The reduction of oxygen levels (hypoxia) in tissues due to an inadequate blood supply.

EXCITOTOXIC CELL DEATH

Neuronal death caused by the hyperstimulation of glutamate-gated ion channels (for example, as a consequence of the depletion of ATP stores under ischaemic conditions) and the consequent toxic rise in intracellular Ca2+.

CATHEPSINS

A group of aspartyl proteases localized primarily to lysosomes that are implicated in necrosis.

OPTIC LOBE

The part of the adult fly brain that processes sensory information from the compound eye.

TAOPATHY

A group of disorders associated with abnormal accumulation of hyper-phosphorylated microtubule binding protein tau in intracellular neurofibrillary tangles.

AMYLOID PLAQUES

Extracellular, insoluble aggregations of Aβ1-42-fragment, cleaved from the amyloid precursor protein (APP), that accumulate in the brains of Alzheimer disease patients.

PEROXISOME

An organelle that contains machinery to oxidize organic compounds. The site of H202 production and destruction.

LIMBIC CORTEX

The regions of the brain that are associated with emotion.

ASSOCIATION CORTEX

The regions of the brain that are involved in the processing and integration of sensory and sensorimotor information.

GLIAL CELLS

The specialized cells of the central nervous system that are associated with neurons and provide mechanical support, supply nutrients, oxygen and growth factors, and eliminate potentially harmful metabolites and neurotransmitters.

BRADYKINESIA

Slow movement — a symptom associated with Parkinson disease.

DYSTONIA

A disease associated with muscle spasms and twisting of the arms and head.

CHOREA

Involuntary jerky movements of the head, face or limbs, which are characteristic of Huntington disease.

PHOTOTAXIS

Movement towards a light source. Phototaxis assays test locomotor activity in flies.

SUBSTANTIA NIGRA

(SN). The region of the brain that includes the pars compacta, harbouring the neurons that produce the neurotransmitter dopamine required for controlled locomotion. SN neurons degenerate in Parkinson disease.

LOCUS CERULEUS

The area of the brainstem that undergoes degeneration in Parkinson disease.

LEWY STRUCTURES

The intracellular inclusions that function as histological markers for degenerating neurons in the brains of individuals with certain neurodegenerative disorders, including Parkinson disease.

DOPAMINERGIC

Neurons that use dopamine as a neurotransmitter.

PROTOFILAMENTS

The ordered insoluble structures formed by Aβ fragments. In Alzheimer disease, Aβ fragments dimerize and then multimerize into antiparallel β-sheets that form helical protofilaments.

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Driscoll, M., Gerstbrein, B. Dying for a cause: invertebrate genetics takes on human neurodegeneration. Nat Rev Genet 4, 181–194 (2003). https://doi.org/10.1038/nrg1018

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