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Activation of microtubule dynamics increases neuronal growth via the nerve growth factor (NGF)- and G?s-mediated signaling pathways.

ABSTRACT: Signals that activate the G protein G?s and promote neuronal differentiation evoke G?s internalization in rat pheochromocytoma (PC12) cells. These agents also significantly increase G?s association with microtubules, resulting in an increase in microtubule dynamics because of the activation of tubulin GTPase by G?s. To determine the function of G?s/microtubule association in neuronal development, we used real-time trafficking of a GFP-G?s fusion protein. GFP-G?s concentrates at the distal end of the neurites in differentiated living PC12 cells as well as in cultured hippocampal neurons. G?s translocates to specialized membrane compartments at tips of growing neurites. A dominant-negative G? chimera that interferes with G?s binding to tubulin and activation of tubulin GTPase attenuates neurite elongation and neurite number both in PC12 cells and primary hippocampal neurons. This effect is greatest on differentiation induced by activated G?s. Together, these data suggest that activated G?s translocates from the plasma membrane and, through interaction with tubulin/microtubules in the cytosol, is important for neurite formation, development, and outgrowth. Characterization of neuronal G protein dynamics and their contribution to microtubule dynamics is important for understanding the molecular mechanisms by which G protein-coupled receptor signaling orchestrates neuronal growth and differentiation.

SUBMITTER: Sarma T

PROVIDER: S-EPMC4400321 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature

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Activation of microtubule dynamics increases neuronal growth via the nerve growth factor (NGF)- and Gαs-mediated signaling pathways.

Sarma Tulika T Koutsouris Athanasia A Yu Jiang Zhu JZ Krbanjevic Aleksandar A Hope Thomas J TJ Rasenick Mark M MM

The Journal of biological chemistry 20150217 16

Signals that activate the G protein Gαs and promote neuronal differentiation evoke Gαs internalization in rat pheochromocytoma (PC12) cells. These agents also significantly increase Gαs association with microtubules, resulting in an increase in microtubule dynamics because of the activation of tubulin GTPase by Gαs. To determine the function of Gαs/microtubule association in neuronal development, we used real-time trafficking of a GFP-Gαs fusion protein. GFP-Gαs concentrates at the distal end of ...[more]

PMID: 25691569

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Project description:Alzheimer disease (AD) is the most common neurodegenerative disorder and lacks effective disease-modifying therapies. In 2001, we initiated a clinical trial of nerve growth factor (NGF) gene therapy in AD, the first effort at gene delivery in an adult neurodegenerative disorder. This program aimed to determine whether a nervous system growth factor prevents or reduces cholinergic neuronal degeneration in patients with AD. We present postmortem findings in 10 patients with survival times ranging from 1 to 10 years after treatment.To determine whether degenerating neurons in AD retain an ability to respond to a nervous system growth factor delivered after disease onset.Patients in this anatomicopathological study were enrolled in clinical trials from March 2001 to October 2012 at the University of California, San Diego, Medical Center in La Jolla. Ten patients with early AD underwent NGF gene therapy using ex vivo or in vivo gene transfer. The brains of all 8 patients in the first phase 1 ex vivo trial and of 2 patients in a subsequent phase 1 in vivo trial were examined.Brains were immunolabeled to evaluate in vivo gene expression, cholinergic neuronal responses to NGF, and activation of NGF-related cell signaling. In 2 patients, NGF protein levels were measured by enzyme-linked immunosorbent assay.Among 10 patients, degenerating neurons in the AD brain responded to NGF. All patients exhibited a trophic response to NGF in the form of axonal sprouting toward the NGF source. Comparing treated and nontreated sides of the brain in 3 patients who underwent unilateral gene transfer, cholinergic neuronal hypertrophy occurred on the NGF-treated side (P?<?.05). Activation of cellular signaling and functional markers was present in 2 patients who underwent adeno-associated viral vectors (serotype 2)-mediated NGF gene transfer. Neurons exhibiting tau pathology and neurons free of tau expressed NGF, indicating that degenerating cells can be infected with therapeutic genes, with resultant activation of cell signaling. No adverse pathological effects related to NGF were observed.These findings indicate that neurons of the degenerating brain retain the ability to respond to growth factors with axonal sprouting, cell hypertrophy, and activation of functional markers. Sprouting induced by NGF persists for 10 years after gene transfer. Growth factor therapy appears safe over extended periods and merits continued testing as a means of treating neurodegenerative disorders.

Dataset Information

Activation of microtubule dynamics increases neuronal growth via the nerve growth factor (NGF)- and G?s-mediated signaling pathways.

Publications

Activation of microtubule dynamics increases neuronal growth via the nerve growth factor (NGF)- and Gαs-mediated signaling pathways.

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