期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2014
卷号：111
期号：44
页码：15729-15734
DOI：10.1073/pnas.1410274111
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceDamage of the central nervous system (CNS) and neurodegenerative disorders represent the principal cause of morbidity and mortality among adults. An injured CNS is unable to regenerate dendritic or neurite connections because they spontaneously occur in the peripheral nervous system. Inhibitory influences of the glial cells and of myelin-associated inhibitors oppose the spontaneous regeneration of CNS neurons. Here, we identify a positive mechanism of neuronal differentiation, which acts in response to activation of intracellular pathway(s) to remove an inhibitory constraint of neurite outgrowth. Unveiling the molecular events regulating the regenerative capacity of neurons will impact on therapeutic initiatives to stem the course of brain damage or neurodegeneration. Protein kinase A (PKA) controls major aspects of neurite outgrowth and morphogenesis and plays an essential role in synaptic plasticity and memory. However, the molecular mechanism(s) of PKA action on neurite sprouting and activity are still unknown. Here, we report that in response to neurotrophin or cAMP stimulation the RING ligase praja2 ubiquitinates and degrades NOGO-A, a major inhibitor of neurite outgrowth in mammalian brain. Genetic silencing of praja2 severely inhibited neurite extension of differentiating neuroblastoma cells and mesencephalic neurons and axon outgrowth and sprouting of striatal terminals in developing rat brain. This phenotype was rescued when both praja2 and NOGO-A were depleted, suggesting that NOGO-A is, indeed, a biologically relevant target of praja2 in neuronal cells. Our findings unveil a novel mechanism that functionally couples cAMP signaling with the proteolytic turnover of NOGO-A, positively impacting on neurite outgrowth in mammalian brain.
