Evidence that Par-4 participates in the pathogenesis of HIV encephalitis.
Progressive neuronal degeneration in brain regions involved in learning and memory processes is a common occurrence in patients infected with human immunodeficiency virus type 1 (HIV-1). We now report that levels of Par-4, a protein recently linked to neuronal apoptosis in Alzheimer's disease, are increased in neurons in hippocampus of human patients with HIV encephalitis and in monkeys infected with a chimeric strain of HIV-1 and simian immunodeficiency virus. Par-4 levels increased rapidly in cultured hippocampal neurons following exposure to the neurotoxic HIV-1 protein Tat, and treatment of the cultures with a Par-4 antisense oligonucleotide protected the neurons against Tat-induced apoptosis. Additional findings show that Par-4 participates at an early stage of Tat-induced neuronal apoptosis before caspase activation, oxidative stress, and mitochondrial dysfunction. Our data suggest that Par-4 may be a mediator of neuronal apoptosis in HIV encephalitis and that therapeutic approaches targeting the Par-4 apoptotic cascade may prove beneficial in preventing neuronal degeneration and associated dementia in patients infected with HIV-1.
Kruman
I I
II
Sanders-Brown Research Center on Aging, Department of Neurology, Lexington, Kentucky, USA.
Nath
A
A
Maragos
W F
WF
Chan
S L
SL
Jones
M
M
Rangnekar
V M
VM
Jakel
R J
RJ
Mattson
M P
MP
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D002478:Cells, Cultured; D002678:Chimera / Q000502:physiology; D004660:Encephalitis / Q000378:metabolism / Q000821:virology*; D015696:Gene Products, tat / Q000037:antagonists & inhibitors / Q000494:pharmacology; D006678:HIV / Q000235:genetics; D015658:HIV Infections / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008253:Macaca mulatta / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016097:Simian Acquired Immunodeficiency Syndrome / Q000378:metabolism; D054322:tat Gene Products, Human Immunodeficiency Virus
D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins; D015696:Gene Products, tat; D047908:Intracellular Signaling Peptides and Proteins; D016376:Oligonucleotides, Antisense; C101296:prostate apoptosis response-4 protein; D054322:tat Gene Products, Human Immunodeficiency Virus