Abstract
In the brain, both HIV-1 and methamphetamine (meth) use result in increases in oxidative and nitrosative stress. This redox stress is thought to contribute to the pathogenesis of HIV-associated neurocognitive disorder (HAND) and further worsening cognitive activity in the setting of drug abuse. One consequence of such redox stress is aberrant protein S-nitrosylation, derived from nitric oxide, which may disrupt normal protein activity. Here, we report an improved, mass spectrometry-based technique to assess S-nitrosylated protein in human postmortem brains using selective enrichment of S-nitrosocysteine residues with an organomercury resin. The data show increasing S-nitrosylation of tricarboxylic acid (TCA) enzymes in the setting of HAND and HAND/meth use compared with HIV+ control brains without CNS pathology. The consequence is systematic inhibition of multiple TCA cycle enzymes, resulting in energy collapse that can contribute to the neuronal and synaptic damage observed in HAND and meth use.
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03 May 2021
A Correction to this paper has been published: https://doi.org/10.1007/s13365-021-00985-x
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Funding
This work was supported in part by NIH grants R01 NS086890, DP1 DA041722, RF1 AG057409, and R01 AG056259 (to S.A.L.) and R01 AG061845 (to T.N.). We thank Eliezer Masliah (UC San Diego/NIA) for providing human brain tissues as part of the National NeuroAIDS Tissue Network and Ben Gouaux and Cristian Achim (UC San Diego) for supplying information on these tissues. The NNTC was in part supported by NIH funding from NIMH and NINDS by the following grants: Manhattan HIV Brain Bank (MHBB) U24MH100931, Texas NeuroAIDS Research Center (TNRC) U24MH100930, National Neurological AIDS Bank (NNAB) U24MH100929, California NeuroAIDS Tissue Network (CNTN) U24MH100928, and the Data Coordinating Center (DCC) U24MH100925.
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Doulias, PT., Nakamura, T., Scott, H. et al. TCA cycle metabolic compromise due to an aberrant S-nitrosoproteome in HIV-associated neurocognitive disorder with methamphetamine use. J. Neurovirol. 27, 367–378 (2021). https://doi.org/10.1007/s13365-021-00970-4
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DOI: https://doi.org/10.1007/s13365-021-00970-4