Human immunodeficiency virus type 1 alters brain-derived neurotrophic factor processing in neurons.
The molecular mechanisms leading to synaptic simplification and neuronal apoptosis in human immunodeficiency virus type 1 (HIV-1)-positive subjects are unknown. The HIV protein gp120 reduced the length of neuronal processes similarly to the proneurotrophin pro-brain-derived neurotrophic factor (proBDNF). Intriguingly, the effects of both proBDNF and gp120 were blocked by inhibitors of the p75 neurotrophin receptor, suggesting that proBDNF and gp120 share a similar mechanism of neurotoxicity. Therefore, we tested the hypothesis that gp120 affects the release of proBDNF. Using rat primary neurons, we observed that gp120 promotes a time-dependent intracellular and extracellular accumulation of proBDNF concomitantly with a decrease in mature BDNF. A similar imbalance in the ratio proBDNF/mature BDNF was confirmed in postmortem brains of HIV-positive subjects cognitively impaired and motor impaired. Therefore, it is conceivable to formulate the hypothesis that HIV neurotoxicity includes a gp120-mediated alteration of BDNF processing. To determine the cellular mechanism whereby gp120 produces an accumulation of proBDNF, we examined the levels of intracellular and extracellular enzymes that proteolytically cleave proBDNF furin and tissue plasminogen, respectively. In rat neurons exposed to gp120, intracellular furin levels decreased before cell death, whereas tissue plasminogen changed only during apoptosis. Our data suggest that HIV, through gp120, reduces proBDNF processing by affecting furin levels, and therefore causes an altered balance between antiapoptotic and proapoptotic neurotrophins. Our studies identify a new mechanism that may explain how HIV promotes neuronal injury.
Department of Neuroscience, Georgetown University Medical Center, Washington, DC 20057, USA.
Alessia
A
Bachis
Valeriya
V
Avdoshina
Luigi
L
Zecca
Maia
M
Parsadanian
Italo
I
Mocchetti
D000293:Adolescent; D000328:Adult; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D002227:Carbazoles / Q000494:pharmacology; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D015699:HIV Envelope Protein gp120 / Q000494:pharmacology; D015658:HIV Infections / Q000378:metabolism / Q000473:pathology; D015497:HIV-1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D026121:Indole Alkaloids / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D016501:Neurites / Q000187:drug effects; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism* / Q000821:virology*; D010455:Peptides / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017475:Receptors, Nerve Growth Factor / Q000235:genetics / Q000378:metabolism; D013997:Time Factors
D019208:Brain-Derived Neurotrophic Factor; D002227:Carbazoles; D004791:Enzyme Inhibitors; D015699:HIV Envelope Protein gp120; D026121:Indole Alkaloids; D010455:Peptides; D017475:Receptors, Nerve Growth Factor; C517634:Ngfr protein, mouse; C049985:staurosporine aglycone