Activation of cyclin-dependent kinase 5 by calpains contributes to human immunodeficiency virus-induced neurotoxicity.
Although the specific mechanism of neuronal damage in human immunodeficiency virus (HIV) -associated dementia is not known, a prominent role for NMDA receptor (NMDAR)-induced excitotoxicity has been demonstrated in neurons exposed to HIV-infected/activated macrophages. We hypothesized NMDAR-mediated activation of the calcium-dependent protease, calpain, would contribute to cell death by induction of cyclin-dependent kinase 5 (CDK5) activity. Using an in vitro model of HIV neurotoxicity, in which primary rat cortical cultures are exposed to supernatants from primary human HIV-infected macrophages, we have observed increased calpain-dependent cleavage of the CDK5 regulatory subunit, p35, to the constitutively active isoform, p25. Formation of p25 is dependent upon NMDAR activation and calpain activity and is coincident with increased CDK5 activity in this model. Further, inhibition of CDK5 by roscovitine provided neuroprotection in our in vitro model. Consistent with our observations in vitro, we have observed a significant increase in calpain activity and p25 levels in midfrontal cortex of patients infected with HIV, particularly those with HIV-associated cognitive impairment. Taken together, our data suggest calpain activation of CDK5, a pathway activated in HIV-infected individuals, can mediate neuronal damage and death in a model of HIV-induced neurotoxicity.
Wang
Ying
Y
Department of Pathology, School of Dental Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
White
Michael G
MG
Akay
Cagla
C
Chodroff
Rebecca A
RA
Robinson
Jonathan
J
Lindl
Kathryn A
KA
Dichter
Marc A
MA
Qian
Yang
Y
Mao
Zixu
Z
Kolson
Dennis L
DL
Jordan-Sciutto
Kelly L
KL
D015526:AIDS Dementia Complex / Q000378:metabolism* / Q000473:pathology*; D000818:Animals; D015153:Blotting, Western; D002154:Calpain / Q000494:pharmacology*; D002452:Cell Count; D016923:Cell Death; D002478:Cells, Cultured; D004396:Coloring Agents; D051360:Cyclin-Dependent Kinase 5 / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay; D015497:HIV-1; D007202:Indicators and Reagents; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D009000:Monocytes / Q000737:chemistry; D009474:Neurons / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013347:Subcellular Fractions / Q000378:metabolism
D004396:Coloring Agents; D007202:Indicators and Reagents; D016194:Receptors, N-Methyl-D-Aspartate; D051360:Cyclin-Dependent Kinase 5; D019950:Mitogen-Activated Protein Kinase 1; D002154:Calpain