title: The effects of short-term JNK inhibition on the survival and growth of aged sympathetic neurons.
abstract: During the course of normal aging, certain populations of nerve growth factor (NGF)-responsive neurons become selectively vulnerable to cell death. Studies using dissociated neurons isolated from neonates have shown that c-Jun N-terminal kinases (JNKs) are important in regulating the survival and neurite outgrowth of NGF-responsive sympathetic neurons. Unlike neonatal neurons, adult sympathetic neurons are not dependent on NGF for their survival. Moreover, the NGF precursor, proNGF, is neurotoxic for aging but not young adult NGF-responsive neurons. Because of these age-related differences, the effects of JNK inhibition on the survival and growth of sympathetic neurons isolated from aged mice were studied. Aged neurons, as well as glia, were found to be dependent on JNK for their growth but not their survival. Conversely, proNGF neurotoxicity was JNK-dependent and mediated by the p75-interacting protein NRAGE, whereas neurite outgrowth was independent of NRAGE. These results have implications for the potential use of JNK inhibitors as therapies for ameliorating age-related neurodegenerative disease.
authors.affiliation: Genetics Unit and Wolfson Drug Discovery Unit, Centre for Amyloidosis and Acute Phase Proteins, Division of Medicine, University College London, Royal Free Campus, London, UK.
authors.forename: Isa
authors.initials: I
authors.lastname: Guha
authors.affiliation: Genetics Unit and Wolfson Drug Discovery Unit, Centre for Amyloidosis and Acute Phase Proteins, Division of Medicine, University College London, Royal Free Campus, London, UK.
authors.forename: Ivana
authors.initials: I
authors.lastname: Slamova
authors.affiliation: Genetics Unit and Wolfson Drug Discovery Unit, Centre for Amyloidosis and Acute Phase Proteins, Division of Medicine, University College London, Royal Free Campus, London, UK.
authors.forename: Soyon
authors.initials: S
authors.lastname: Chun
authors.affiliation: Genetics Unit and Wolfson Drug Discovery Unit, Centre for Amyloidosis and Acute Phase Proteins, Division of Medicine, University College London, Royal Free Campus, London, UK.
authors.forename: Arthur
authors.initials: A
authors.lastname: Clegg
authors.affiliation: Genetics Unit and Wolfson Drug Discovery Unit, Centre for Amyloidosis and Acute Phase Proteins, Division of Medicine, University College London, Royal Free Campus, London, UK.
authors.forename: Michal
authors.initials: M
authors.lastname: Golos
authors.affiliation: Research Department of Cell and Developmental Biology, University College London, London, UK.
authors.forename: Chris
authors.initials: C
authors.lastname: Thrasivoulou
authors.affiliation: Genetics Unit and Wolfson Drug Discovery Unit, Centre for Amyloidosis and Acute Phase Proteins, Division of Medicine, University College London, Royal Free Campus, London, UK. Electronic address: p.simons@ucl.ac.uk.
authors.forename: J Paul
authors.initials: JP
authors.lastname: Simons
authors.affiliation: Genetics Unit and Wolfson Drug Discovery Unit, Centre for Amyloidosis and Acute Phase Proteins, Division of Medicine, University College London, Royal Free Campus, London, UK. Electronic address: r.al-shawi@ucl.ac.uk.
authors.forename: Raya
authors.initials: R
authors.lastname: Al-Shawi
mesh_terms: D000375:Aging / Q000235:genetics* / Q000473:pathology*; D000818:Animals; D016923:Cell Death / Q000235:genetics / Q000502:physiology; D048708:Cell Growth Processes / Q000235:genetics*; D002470:Cell Survival / Q000235:genetics*; D002478:Cells, Cultured; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000502:physiology*; D008297:Male; D008810:Mice, Inbred C57BL; D058990:Molecular Targeted Therapy; D009363:Neoplasm Proteins / Q000502:physiology; D020932:Nerve Growth Factor / Q000502:physiology / Q000633:toxicity; D016501:Neurites / Q000502:physiology; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000628:therapy; D009474:Neurons / Q000166:cytology* / Q000502:physiology*; D011498:Protein Precursors / Q000633:toxicity; D017207:Rats, Sprague-Dawley; D013564:Sympathetic Nervous System / Q000166:cytology*
chemical_list: C486541:Maged1 protein, mouse; D009363:Neoplasm Proteins; D011498:Protein Precursors; D020932:Nerve Growth Factor; D048031:JNK Mitogen-Activated Protein Kinases
keywords: Aging; JNK; NGF; NRAGE; Neurons; ProNGF