Neurotoxic and neurotrophic roles of proNGF and the receptor sortilin in the adult and ageing nervous system.
The precursor form of the nerve growth factor (proNGF), forms a heterotrimeric complex with the receptors p75 and sortilin; this complex has been implicated in neuron cell death. However, it is not known whether proNGF and the receptors p75 and sortilin contribute to age- and disease-related neurodegeneration. Here we show that proNGF induces cell death in subpopulations of basal forebrain and peripheral sympathetic neurons of old, but not of young, adult rodents. In contrast, proNGF appears to induce neurite outgrowth rather than cell death of young adult sympathetic neurons. We have examined the neurotoxic role of proNGF in old age, and find that proNGF protein is elevated during ageing in the projection areas of some populations of vulnerable central and peripheral neurons; caloric restriction, which has known neuroprotective effects, partially prevents these increases. Sortilin was found to play a significant part in the observed patterns of age-related proNGF-mediated neurotoxicity. In particular, survival of aged neurons was rescued by neurotensin, an alternative sortilin ligand that blocks the sortilin-mediated effects of proNGF. Furthermore, sortilin immunoreactivity increases markedly in ageing rodent basal forebrain and sympathetic neurons; in contrast, p75 levels are either unchanged or reduced. From these data we propose that selective age-related neuronal atrophy and neurodegeneration may be mediated by increased sortilin expression in neurons, together with elevated levels of proNGF expression in some targets.
Al-Shawi
Raya
R
Centre for Biomedical Sciences, University College London, Hampstead Campus, Rowland Hill Campus, Rowland Hill Street, London NW3 2PF, UK. r.al-shawi@medsch.ucl.ac.uk
Hafner
Angela
A
Olsen
Jessica
J
Olson
Jessica
J
Chun
Soyon
S
Raza
Saba
S
Thrasivoulou
Christopher
C
Lovestone
Simon
S
Killick
Richard
R
Simons
Paul
P
Cowen
Timothy
T
D033942:Adaptor Proteins, Vesicular Transport; D000368:Aged; D000375:Aging / Q000502:physiology*; D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D000818:Animals; D015153:Blotting, Western; D031204:Caloric Restriction; D002478:Cells, Cultured; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D018613:Microscopy, Confocal; D009410:Nerve Degeneration / Q000503:physiopathology*; D020932:Nerve Growth Factor / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D009924:Organ Culture Techniques; D016548:Prosencephalon / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017978:Receptors, Growth Factor; D017475:Receptors, Nerve Growth Factor / Q000378:metabolism; D000099183:Sortilin
D033942:Adaptor Proteins, Vesicular Transport; D008562:Membrane Glycoproteins; D020932:Nerve Growth Factor; D009419:Nerve Tissue Proteins; D017978:Receptors, Growth Factor; D017475:Receptors, Nerve Growth Factor; D000099183:Sortilin; C068313:Ngfr protein, rat