YWHAE/14-3-3ε: a potential novel genetic risk factor and CSF biomarker for HIV neurocognitive impairment

Abstract

YWHAE (14-3-3ε) protein levels are considered to be a reliable biomarker for neurodegeneration. The YWHAE protein interacts both directly and indirectly with human immunodeficiency virus (HIV) accessory proteins, leading to cell death. The purpose of this study was to examine the relationship between YWHAE polymorphisms and HIV-associated neurocognitive disorder (HAND) and the relationship between YWHAE protein levels and HAND. A cross-sectional study using random samples of HIV-seropositive (n = 20) and HIV-seronegative (controls) (n = 16) women from the Hispanic-Latino Longitudinal Cohort of Women was conducted. Individuals who are HIV-seropositive and heterozygous at the rs4790084/rs1204828 loci in the YWHAE gene were 3× more likely to display reduced cognitive functioning, to have received a HAND diagnosis, and to have less YHWAE protein expressed than homozygotes. Western blots from cerebral spinal fluid indicate that the HIV-seropositive women with HAND expressed 4.5× less YWHAE compared to HIV-seropositive cognitively normal women (94 % sensitivity, 84 % specificity; HIV-seropositive vs. controls). Therefore, polymorphism in YWHAE may be a genetic risk factor for HAND and levels of YWHAE protein are a likely biomarker for neurocognitive status in HIV-seropositive women.

Figure 1. Proposed model of relationship between YWHAE (14-3-3ε) and HIV accessory protein gp120

A. Binding of YWHAE (14-3-3ε) is necessary to prevent apoptosis in neurons via is association with phosphorylated B-cell lymphoma 2 (Bcl-2) antagonist of cell death (BAD) protein bound to Bcl-2, thereby suppressing apoptosis. B. Gp120-dependent dephosphorylation of BAD at Serine-112 prevents YWHAE binding allowing for its association with the Bcl-XL leading to apoptosis. Apoptosis of the neuron leads to the release of YWHAE and its eventual degradation.

Figure 2

Representative western blot of CSF samples. CSF samples were added to 12% SDS-PAGE gel, transferred to PDVF membrane and blotted for YWHAE with subsequent reblots with pan-14-3-3. #1 NIH/3T3 whole cell lysate, #2 HIV-seropositive impaired subject and #3 HIV-seropositive normal subjects.