ALS is the most common motor neuron disorder of adulthood and considered one of the most dramatic diseases encountered in human medicine. The disease is characterized by the degeneration of motor neurons in the spinal cord, brainstem and motor cortex resulting in muscle weakness, atrophy and spasticity. The degenerative process also affects neurons in the frontal cortex, resulting in subtle frontal executive dysfunction in most patients, and in overt frontal dementia in 5 % of them. The disease is relentlessly progressive and leads to loss of ambulation, speech and swallow difficulties and finally respiratory problems. ALS is usually fatal after three to five years of evolution most commonly due to bulbar and respiratory insufficiency.  
In 10 % of patients ALS occurs as a familial, usually autosomal dominant disorder. In about one out of five such pedigrees, the disease is caused by mutations in the SOD1 gene encoding the Cu2+, Zn2+-dependent superoxide dismutase (SOD1). The recently identified mutations in the TAR DNA-binding protein TDP-43 appear to be far less frequent. Several other ALS genes are known, but have been identified in only a handful of patients (1). The etiology of sporadic ALS remains elusive. It is thought to arise from a combination of genetic and possible environmental factors, but the evidence for the latter is absent. To elucidate the genetic contribution, several genome-wide association studies have recently been performed in ALS. In these studies, several risk or protective genes have been identified. The significance of the results remains a matter of debate until the biology of these gene products and their role in motor neuron degeneration has been elucidated.
Transgenic mice, rats, fish, worms and pigs that overexpress mutant SOD1 and develop motor neuron abnormalities have been generated. Mutant SOD1 mice have been studied extensively and have greatly advanced our understanding of motor neuron degeneration.

In a genome wide association study on three unrelated populations, we identified a polymorphism in intron 10 of the ELP3 gene on chromosome 8 to protect against the occurrence of ALS. This gene encodes ELP3, the third of six subunits establishing the elongator complex, that is associated with the RNA polymerase II in the nucleus. Lower expression levels of ELP3 were found in the brain of individuals with the at risk genotype.  In an independent genetic screen in Drosophila, we identified two different loss-of-function mutations in the fly homologue of ELP3, that induce aberrant axonal outgrowth and synaptic abnormalities. In addition, we found that knockdown of ELP3 in the zebrafish induced motor axonal abnormalities, suggesting that low ELP3 expression renders the motor neuron vulnerable to neurodegeneration. These data suggest that low expression of ELP3 makes the neuron vulnerable to neurodegeneration, while high levels make it resistant. This project aims to study the role of ELP3 in neurodegeneration and to elucidate whether interfering with the elongator complex may represent a therapeutic target in ALS.

Excitotoxic motor neuron death is mediated through influx of calcium through calcium-permeable AMPA-type glutamate receptors. In previous studies we have demonstrated the importance of the GluR2 subunit of this receptor for the pathogenesis of ALS (2), and have shown it to be regulated through intercellular communication between astrocytes and motor neurons (3). In this project we aim to study the factors involved in the crosstalk between neurons and glial cells and to identify factors that upregulate GluR2 expression. In addition, in an association study of three different populations (Dutch, Swedish and Belgian), we found a very strong association between a single nucleotide polymorphism (SNP) in intron 42 of ITPR2 on chromosome 12p11 and the occurrence of ALS (4). The nature of this association is unknown, but mRNA levels of ITPR2 were significantly higher in ALS patients than in controls. ITPR2 encodes the type 2 receptor for inositol triphosphate (IP3), a receptor in the endoplasmic reticulum (ER) that releases Ca2+ upon stimulation by IP3, and that plays a role in the regulation of autophagy. How ITPR2 expression levels can contribute to motor neuron degeneration is unknown, and is the focus of this project.

In order to identify genes that protect against mutant SOD1-induced neurodegeneration, we established a zebrafish model for ALS (5). In the zebrafish, mutant SOD1 induces a motor axonopathy that can be scored easily. In this project we screen a library of morpholinos in order to identify genes of which knockdown corrects the mutant SOD1 phenotype.

Null mutations in the PGRN gene are a cause of frontotemporal lobar degeneration (FTLD), possibly accounting for 40 % of familial FTLD cases. Some of the patients with PGRN-related FTLD have motor neuron degeneration We have previously identified missense mutations in PGRN in ALS patients and found that a polymorphism in intron 2 (IVS2+21G>A) is associated with a later onset of ALS and a longer survival (6).
The nature of the mutations in FTLD suggests a non-functional mutated, which, in view of its dominant nature of inheritance, implies haplo-insufficiency. This is also supported by our finding that PGRN levels in FTLD patients with null mutations are  50 % of that of controls (7), How low levels of PGRN could lead to frontal and motor neuron loss is not understood. PGRN is a secreted precursor protein that is expressed in many tissues and is thought to play a role in wound healing, oncogenesis, inflammation and development We have demonstrated it to be a trophic factor for cortical and motor neurons in vitro: it increased survival and promoted neurite outgrowth in cultured neurons from mouse spinal cord and cortex (7).
The biology of PGRN processing, the receptor it interacts with, the signaling pathways and the effects of PGRN in the adult nervous system are unknown and are the focus of this project.

The spinal cord of patients with ALS is characterized by an impressive activation of glial cells, both astrocytes and microglia. It is thought that these cells contribute to the pathogenesis of the motor neuron degeneration, but remains unclear how this happens. It is important to elucidate this process, as interfering with glial activation, or transplanting healthy glial cells in the diseased spinal cord is feasible in animal models and may become feasible in patients. In the present project we investigate the mechanism of astrocytic activation and the contribution of microglial cells to ALS.

In collaboration with the university hospital Leuven we are investigating new therapeutic avenues for patients with ALS.

VEGF as a treatment for ALS
We have previously demonstrated the possible role of vascular endothelial growth factor (VEGF) in the pathogenesis of ALS and showed it to be a trophic factor for motor neurons. We also demonstrated the therapeutic effect of VEGF in rats with ALS. We now are developing the use of intracerebroventricularly administrated VEGF for patients with ALS. This program is now in the stage of phase 1 studies done in collaboration with Neuronova Ltd. More information on this trial can be obtained at www.neurology-kuleuven.be and at This e-mail address is being protected from spam bots, you need JavaScript enabled to view it