Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0002736 (amyotrophic lateral sclerosis)
 19,048 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Astrocytes may modulate the survival of motor neurons in amyotrophic lateral sclerosis (ALS). We have previously shown that fibroblast growth factor-1 (FGF-1) activates astrocytes to increase secretion of nerve growth factor (NGF). NGF in turn induces apoptosis in co-cultured motor neurons expressing the p75 neurotrophin receptor (p75NTR) by a mechanism involving nitric oxide (NO) and peroxynitrite formation. We show here that FGF-1 increased the expression of inducible nitric oxide synthase and NO production in astrocytes, making adjacent motor neurons vulnerable to NGF-induced apoptosis. Spinal cord astrocytes isolated from transgenic SOD1G93A rats displayed increased NO production and spontaneously induced apoptosis of co-cultured motor neurons. FGF-1 also activates the redox-sensitive transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) in astrocytes. Because Nrf2 increases glutathione (GSH) biosynthesis, we investigated the role of GSH production by astrocytes on p75NTR-dependent motor neuron apoptosis. The combined treatment of astrocytes with FGF-1 and t-butylhydroquinone (tBHQ) increased GSH production and secretion, preventing motor neuron apoptosis. Moreover, Nrf2 activation in SOD1G93A astrocytes abolished their apoptotic activity. The protection exerted by increased Nrf2 activity was overcome by adding the NO donor DETA-NONOate to the co-cultures or by inhibiting GSH synthesis and release from astrocytes. These results suggest that activation of Nrf2 in astrocytes can reduce NO-dependent toxicity to motor neurons by increasing GSH biosynthesis.
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PMID:Increased glutathione biosynthesis by Nrf2 activation in astrocytes prevents p75NTR-dependent motor neuron apoptosis. 1652 72

The control of polarized human neurite/axon development at the single neuron level is critical in geographically directing signal propagation in engineered neural networks, for both in vitro and in vivo applications. While there is an increasing need to exert control over axonal growth for the successful development and establishment of integrative and functional in vitro systems, controlled, polarized distribution of either human-derived neurons or motoneurons in vitro has yet to be reported. In this study, we established the polarized distribution of stem cell derived human motoneurons, using a patterned surface, and maintained the cells in a serum-free system. A surface pattern with defined polarity was developed using self-assembled monolayers (SAMs). A cell permissive SAM, DETA (trimethoxysilyl propyldiethylenetri-amine), combined with photolithography and a nonpermissive fluorinated silane, 13F (tridecafluoro-1,1,2,2-tetrahydroctyl-1-dimethylchloro-silane), generated a surface where neurons only adhered to the designed attachment sites and did so with preferred orientation. In addition, 75% of the cells attached to the patterns were motoneurons compared to their percentage in the standard unpatterned surface which was used as a control condition (20%), demonstrating the preference of these human motoneurons in adhering to the patterns. The ability to dictate the distribution and polarity of human motoneurons will be essential to the engineering of human-based functional in vitro systems in which the control of signal propagation is necessary but more importantly for cell implantation studies. Such systems will greatly benefit the study of motor function as well as aid the development of high-throughput systems for drug screening and test beds for use in preclinical studies related to conditions such as spinal cord injury, ALS, and muscular dystrophy.
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PMID:Polarity Induced in Human Stem Cell Derived Motoneurons on Patterned Self-Assembled Monolayers. 3106 82