Marcel van den Heuvel

The Fly as a Model for Neurodegenerative Diseases: Is It Worth the Jump?

Neurodegenerative diseases are responsible for agonizing symptoms that take their toll on the fragile human life. Aberrant protein processing and accumulation are considered to be the culprits of many classical neurodegenerative diseases such as Alzheimer’s disease, tauopathies, Parkinson’s disease, amyotrophic lateral sclerosis, hereditary spastic paraplegia and various polyglutamine diseases. However, recently it has been shown that toxic RNA species or disruption of RNA processing and metabolism may be partly to blame as clearly illustrated in spinal muscular atrophy, spinocerebellar ataxia 8 and fragile X-associated tremor/ataxia syndrome. At the dawn of the twenty-first century, the fruit fly or Drosophila melanogaster has taken its place at the forefront of an uphill struggle to unveil the molecular and cellular pathophysiology of both protein- and RNA-induced neurodegeneration, as well as discovery of novel drug targets. We review here the various fly models of neurodegenerative conditions, and summarise the novel insights that the fly has contributed to the field of neuroprotection and neurodegeneration.

Disruption of SMN function by ectopic expression of the human SMN gene in Drosophila.

Spinal muscular atrophy is a neurodegenerative disorder caused by mutations or deletions in the survival motor neuron (SMN) gene. We have cloned the Drosophila ortholog of SMN (DmSMN) and disrupted its function by ectopically expressing human SMN. This leads to pupal lethality caused by a dominant‐negative effect, whereby human SMN may bind endogenous DmSMN resulting in non‐functional DmSMN/human SMN hetero‐complexes. Ectopic expression of truncated versions of DmSMN and yeast two‐hybrid analysis show that the C‐terminus of SMN is necessary and sufficient to replicate this effect. We have therefore generated a system which can be utilized to carry out suppressor and high‐throughput screens, and provided in vivo evidence for the importance of SMN oligomerization for SMN function at the level of an organism as a whole.

Differential range and activity of various forms of the Hedgehog protein

BackgroundThe Hedgehog (Hh) family of secreted proteins act as extracellular messengers to control and coordinate growth and differentiation. The mechanism by which Hh protein travels across a field of cells, and results in a range of specific effects relating to the distance from the source, has been the subject of much debate. It has been suggested that the range and activity of the pathway can be linked to modifications of the Hh protein, specifically the addition of lipid groups at N- and C-terminal sites.ResultsHere we have addressed the potency of different forms of Hh protein by expressing these in Drosophila, where we are able to precisely establish pathway activity and range in naïve but responsive tissues. As expected, a construct that can produce all forms of Hh recapitulates endogenous signaling potencies. In comparison, expression of a form that lacks the cholesterol moiety (HhN) leads to an extended range, but the product is less effective at inducing maximal Hh responses. Expression of a point mutant that lacks the N-terminal palmitate binding site shows that the palmitoylation of Hh is absolutely required for activity in this system.ConclusionWe conclude that the addition of the cholesterol moiety limits the range of the protein and is required for maximal activity, while addition of palmitate is required for all activity. These findings have implications for understanding how Hedgehog proteins move, and thus their potential at influencing distant sites, and concomitantly, how modifications of the signaling protein can affect the efficacy of the response in exposed cells.

Straight or split: signals to transcription

Since the discovery of substances in serum media that are able to drive cells into proliferation and/or differentiation, investigators have tried to understand how such signalling molecules can influence cells to change their behaviour. The complex nature of the responses to signals, and the equally complex signalling pathway leading to those responses, have made life difficult for the researcher. However, recent evidence obtained in genetic developmental systems indicates that a multiplicity of downstream events can be accomplished by regulation of the activity of just one transcription factor.Since the discovery of substances in serum media that are able to drive cells into proliferation and/or differentiation, investigators have tried to understand how such signalling molecules can influence cells to change their behaviour. The complex nature of the responses to signals, and the equally complex signalling pathway leading to those responses, have made life difficult for the researcher. However, recent evidence obtained in genetic developmental systems indicates that a multiplicity of downstream events can be accomplished by regulation of the activity of just one transcription factor.

Hedgehog signalling: off the shelf modulation

Many cell signalling pathways are modulated in important ways by general cellular machineries, such as those mediating protein degradation and translocation. Two recent studies have revealed roles for such mechanisms in the Hedgehog signalling pathway in Drosophila.

Fat hedgehogs, slower or richer?

Hedgehog (Hh) is a protein ligand that is involved in early developmental patterning. The activity of Hh is controlled by cleavage events and various posttranslational modifications, including the addition of cholesterol and palmitic acid. Van den Heuvel describes how acylation of Hh affects the activity of the protein and explores the differences in activity between the vertebrate sonic hedgehog (Shh) and Drosophila Hh.