Dying for VEGF

Abstract

A number of hereditary neurodegenerative diseases, including Huntington's disease, spinal and bulbar muscular atrophy (SBMA), and the spinocerebellar ataxias, are associated with genes containing an expanded trinucleotide CAG repeat (which encodes multiple glutamines; see Katsuno and Sobue). Each of these disorders involves a CAG expansion of a distinct gene. SBMA, which is associated with a CAG expansion of the gene that encodes the androgen receptor (AR), affects only males (because of androgen-dependent translocation of AR to the nucleus). CAG repeats are hypothesized to cause neurodegeneration through decreased gene transcription secondary to association of the mutant protein with the transcriptional coactivator cAMP response element-binding protein (CREB)-binding protein (CBP), but it isn't clear which downstream genes are critically involved. Sopher et al. introduced yeast artificial chromosomes containing mutant human AR into embryonic mouse stem cells to obtain a mouse model of SBMA characterized by an adult-onset motor deficit accompanied by lower motor neuron degeneration. Immunohistochemical analysis indicated that mutant AR accumulated in the nuclei of motor neurons. Moreover, mutant AR showed enhanced coimmunoprecipitation with CBP. The authors used reverse transcription polymerase chain reaction and enzyme-linked immunosorbent assay to demonstrate that expression of vascular endothelial growth factor (VEGF, which contains a CBP-regulated promoter element) was decreased in mice expressing the mutant AR. VEGF rescued mutant AR-dependent death of motor neurons in vitro, as did CBP overexpression (which was associated with increased VEGF expression). Thus, decreased expression of VEGF may be involved in the pathogenesis of SBMA, perhaps through enhanced motor neuron susceptibility to stress and injury. B. L. Sopher, P. S. Thomas Jr., M. A. LaFevre-Bernt, I. E. Holm, S. A. Wilke, C. B. Ware, L.-W. Jin, R. T. Libby, L. M. Ellerby, A. R. La Spada, Androgen receptor YAC transgenic mice recapitulate SBMA motor neuronopathy and implicate VEGF164 in the motor neuron degeneration. Neuron 41 , 687-699 (2004). [Online Journal] M. Katsuno, G. Sobue, Polyglutamine diminishes VEGF: Passage to motor neuron death? Neuron 41 , 677-682 (2004). [Online Journal]