transforming-growth-factor-beta and Motor-Neuron-Disease

Transforming growth factor β (TGF-β), a pleiotropic cytokine, regulates a diverse range of cellular responses, such as proliferation, differentiation, migration, and apoptosis. The TGF-β1, -β2, and -β3 isoforms are expressed by neurons and glial cells, and their receptors are expressed throughout the central nervous system. Several lines of evidence demonstrate that TGF-β signaling protects neurons from glutamate-mediated excitotoxicity, a putative mechanism underlying the pathogenesis of various neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS). Recent studies indicate that the TGF-β-Smad2/3 pathway restores motor function in a mouse model of ALS, and that disruption of TGF-β signaling due to the transcriptional dysregulation of its receptor is associated with polyglutamine-induced motor neuron damage in spinal and bulbar muscular atrophy. Moreover, the TGF-β-Smad2/3 pathway regulates the function of glial cells, although the implication of this regulation in neurodegeneration remains elusive. Conversely, myostatin, a member of the TGF-β superfamily, has gained attention as a potential therapeutic target for neuromuscular disorders because genetic deletion of this factor results in increased muscle volume. Signal transduction by BMP, a member of the TGF-β super family, regulates the function and growth of the neuromuscular junction, while the disruption of this signaling has been reported in animal models of hereditary spastic paraplegia. These findings support the hypothesis that the disruption of TGF-β 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.

Topics: Animals; Humans; Motor Neuron Disease; Motor Neurons; Muscle, Skeletal; Neuromuscular Junction; Receptors, Transforming Growth Factor beta; Signal Transduction; Spastic Paraplegia, Hereditary; Transforming Growth Factor beta

Proliferation of glia and immune cells is a common pathological feature of many neurodegenerative diseases including amyotrophic lateral sclerosis (ALS). Here, to investigate the role of proliferating cells in motor neuron disease, SOD1(G93A) transgenic mice were treated intracerebroventicularly (i.c.v.) with the anti-mitotic drug cytosine arabinoside (Ara-C). I.c.v. delivery of Ara-C accelerated disease progression in SOD1(G93A) mouse model of ALS. Ara-C treatment caused substantial decreases in the number of microglia, NG2+ progenitors, Olig2+ cells and CD3+ T cells in the lumbar spinal cord of symptomatic SOD1(G93A) transgenic mice. Exacerbation of disease was also associated with significant alterations in the expression inflammatory molecules IL-1β, IL-6, TGF-β and the growth factor IGF-1.

Topics: Amyotrophic Lateral Sclerosis; Animals; Cell Proliferation; Cytarabine; Disease Models, Animal; Disease Progression; Humans; Insulin-Like Growth Factor I; Interleukin-6; Mice; Mice, Transgenic; Microglia; Motor Neuron Disease; Superoxide Dismutase; Transforming Growth Factor beta

We have used adult rat peripheral nerve avulsion models to evaluate the effects of neuroprotective molecules on motoneuron degeneration. The right facial nerves of adult Fischer 344 male rats were avulsed and adenoviral vectors encoding glial cell line-derived neurotrophic factor (GDNF), brain-derived neurotrophic factor (BDNF), transforming growth factor-beta2 (TGFbeta2), and growth inhibitory factor (GIF) were injected into the facial canal. The treatment with the vectors significantly prevented the loss of lesioned facial motoneurons, improved choline acetyltransferase (ChAT) immunoreactivity and suppressed the induction of nitric oxide synthase activity in these neurons. In separate experiments, animals were orally administered a solution of a neuroprotective compound T-588 after avulsion. Both free oral administration and oral tube administration of T-588 improved the survival of injured motoneurons and ameliorated their ChAT immunoreactivity. These results indicate that the gene transfer of GDNF, BDNF, TGFbeta2, and GIF and oral administration of T-588 may prevent the degeneration of motoneurons in adult humans with motoneuron injury and motor neuron diseases.

Topics: Adenoviridae; Animals; Brain-Derived Neurotrophic Factor; Diethylamines; Disease Models, Animal; Facial Nerve Injuries; Gene Transfer Techniques; Genetic Vectors; Glial Cell Line-Derived Neurotrophic Factor; Male; Metallothionein 3; Motor Neuron Disease; Motor Neurons; Nerve Degeneration; Nerve Tissue Proteins; Neuroprotective Agents; Peripheral Nerve Injuries; Peripheral Nerves; Rats; Thiophenes; Transforming Growth Factor beta

The Wobbler mouse, a model of amyotrophic lateral sclerosis (ALS), presents motorneuron degeneration and pronounced astrogliosis in the spinal cord. We have studied factors controlling astrocyte proliferation in cultures derived from Wobbler and control mice spinal cord. Basal rate of [3H]thymidine incorporation was 15 times lower in Wobbler astrocytes. While in control cultured cells interleukin-1alpha (IL-1) and corticosterone (CORT) significantly increased proliferation, both agents were inactive in Wobbler astrocytes. The lack of response to CORT was not due to the absence of glucocorticoid receptors, because similar receptor amounts were found in Wobbler and control astrocytes. In contrast to IL-1 and CORT, transforming growth factor-beta1 (TGF-beta1) substantially increased proliferation of Wobbler astrocytes but not of control cells. Differences in response to TGF-beta1 were also obtained by measuring glial fibrillary acidic protein (GFAP) immunoreaction intensity, which was substantially higher in Wobbler astrocytes. Thus, abnormal responses to different mitogens characterized Wobbler astrocytes in culture. We suggest that TGF-beta1 may play a role in the reactive gliosis and GFAP hyperexpression found in the degenerating spinal cord of this model of ALS.

Topics: Animals; Astrocytes; Cell Division; Cells, Cultured; Corticosterone; Female; Glial Fibrillary Acidic Protein; Gliosis; Interleukin-1; Kinetics; Male; Mice; Mice, Inbred Strains; Mice, Neurologic Mutants; Motor Neuron Disease; Neuroprotective Agents; Pregnatrienes; Receptors, Glucocorticoid; Reference Values; Spinal Cord; Thymidine; Transforming Growth Factor beta