TGF-beta signaling in neurodegenerative diseases

Transforming growth factor beta (TGF-beta), a pleiotropic cytokine, regulates a diverse range of cellular responses, such as proliferation, differentiation, migration, and apoptosis. Recent studies indicate that disruption of TGF-beta signaling due to the transcriptional dysregulation of its receptor is associated with polyglutamine-induced motor neuron damage in spinal and bulbar muscular atrophy. Moreover, a single-nucleotide polymorphism (SNP) in the promoter region of ZNF512B, a putative regulator of TGF-beta signaling, is shown to be associated with susceptibility to amyotrophic lateral sclerosis. Signal transduction by BMP, a member of the TGF-beta super family, is decreased in a fly model of spinal muscular atrophy, while the abnormal activation of this signaling has been reported in animal models of hereditary spastic paraplegia. These findings support the hypothesis that the disruption of TGF-beta signaling is an important molecular event in the pathogenesis of motor neuron diseases, and that the modification of this signaling pathway represents a new therapeutic strategy against these devastating disorders.