Biomedical subjects

Marcel van den Heuvel

Publications and source records attributed to Marcel van den Heuvel.

5 recordsLinked to original sources

PubMed2006

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.

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PubMed2005

Differential range and activity of various forms of the Hedgehog protein.

BACKGROUND: The 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. RESULTS: Here 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. CONCLUSION: We 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.

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PubMed2004

Fruits and flies: a genomics perspective of an invertebrate model organism.

The increasing number of species for which a full genome sequence is available offers rich pickings for geneticists, but comparative analysis and assembly of information gathered across species does not always lead to answers about the function of a particular gene. This paper aims to place the invertebrate model system--the fly Drosophila melanogaster--into this playing field and to discuss how the organism arrived at its position in functional genetic analysis. Indeed, despite the wealth of knowledge on how a fly lives, breathes and flies, this organism is likely to remain a player in the analysis of biological, disease and pharmaceutical processes. The fast genetics Drosophila offers, combined with a well-annotated genome and a wealth of techniques facilitating gene function discovery, will ensure its place in functional genomics for some time to come. Although the fly cannot speak, it certainly can tell a tale.

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PubMed2003

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.

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PubMed2003

Neuromuscular defects in a Drosophila survival motor neuron gene mutant.

Autosomal recessive spinal muscular atrophy (SMA) is linked to mutations in the survival motor neuron (SMN) gene. The SMN protein has been implicated at several levels of mRNA biogenesis and is expressed ubiquitously. Studies in various model organisms have shown that the loss of function of the SMN gene leads to embryonic lethality. The human contains two genes encoding for SMN protein and in patients one of these is disrupted. It is thought the remaining low levels of protein produced by the second SMN gene do not suffice and result in the observed specific loss of lower motor neurons and muscle wasting. The early lethality in the animal mutants has made it difficult to understand why primarily these tissues are affected. We have isolated a Drosophila smn mutant. The fly alleles contain point mutations in smn similar to those found in SMA patients. We find that zygotic smn mutant animals show abnormal motor behavior and that smn gene activity is required in both neurons and muscle to alleviate this phenotype. Physiological experiments on the fly smn mutants show that excitatory post-synaptic currents are reduced while synaptic motor neuron boutons are disorganized, indicating defects at the neuromuscular junction. Clustering of a neurotransmitter receptor subunit in the muscle at the neuromuscular junction is severely reduced. This new Drosophila model for SMA thus proposes a functional role for SMN at the neuromuscular junction in the generation of neuromuscular defects.

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