The present invention relates to neurological and physiological dysfunction associated with
neuron disorders. In (particular, the invention relates to the involvement of
vascular endothelial growth factor (VEGF) and homologues in the aetiology of
motor neuron disorders. The invention further concerns a novel,
mutant transgenic mouse (VEGFm / m) with a homozygous deletion in the hypoxia responsive element (HRE) of the VEGF
promoter which alters the hypoxic upregulation of VEGF. These mice suffer severe adult onset
muscle weakness due to progressive spinal
motor neuron degeneration which is reminiscent of
amyotrophic lateral sclerosis (ALS)-a fatal disorder with unknown aetiology. Furthermore, the neuropathy of these mice is not caused by vascular defects, but is due to defective VEGF-mediated survival signals to motor neurons. The present invention relates in particular to the isoform VEGF165 which stimulates survival of motor neurons via binding to
neuropilin-1, a
receptor known to bind
semaphorin-3A which is implicated in
axon retraction and neuronal death, and the VEGF
Receptor-2. The present invention thus relates to the usage of VEGF, in particular VEGF165, for the treatment of
neuron disorders and relates, in addition, to the usage of polymorphisms in the VEGF promotor for diagnosing the latter disorders.