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 3X 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 (CSF) indicate that the HIV-seropositive women with HAND expressed 4.5X 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.

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“… 8 14-3-3ε belongs to the 14-3-3 family, which was first identified in mammalian brain tissues by Moor and Perez in 1968. 36 Previous studies have implicated 14-3-3ε as a cell enhancer factor that promotes cell proliferation in breast cancer cells, 12 gastric cancer SGC7901 cells, 37 and hepatocellular carcinoma 14 and as a potential novel genetic risk factor for HIV neurocognitive impairment, 24 major depressive disorder in males of the Chinese Han population, 38 and development of midline craniofacial structures. 39 Recently, Alex and colleagues 9 suggested that 14-3-3ε and other family members play an important role in the development and progression of PCa, indicating that it can be employed as a drug target in the treatment of PCa.…”

“…In addition, 14-3-3ε may serve as a novel prognostic biomarker or therapeutic target for HCC, 14 breast cancer, 12 and HIV neurocognitive impairments. 24 Although previous studies have indicated that 14-3-3ε can be used as drug targets in the treatment of PCa, its specific mechanism remains unclear. Currently, chemotherapeutic drugs that target 14-3-3ε in PCa mainly include docetaxel and a non-peptidic small-molecule inhibitor of SFN known as BV02.…”

Immune Responses in the Central Nervous System Are Anatomically Segregated in a Non-Human Primate Model of Human Immunodeficiency Virus Infection

“…We found downregulation of YWHAE expression in the midbrain of SIV-infected macaques. Although YWHAE is one of the genes which we expected to be upregulated during neurotxicity, based on the definition of the gene array, the protein encoded by YWHAE (14-3-3ε protein) is involved in the inhibition of apoptosis via association with Bcl-2, and CSF levels of YWHAE are reduced in HIV-infected patients who display cognitive impairment (61). The gene expression pattern in the frontal lobe was consistent with the activation of pathways leading to neuronal apoptosis (downregulation of EIF2AK3 and NOTCH4 and upregulation of CASP7) in SIV-infected macaques.…”

Differential Expression Profile of Long Non-coding RNAs during Differentiation of Cardiomyocytes

“…However, some studies have been shown that Ywhae play a critical role in many diseases, such as HIV neurocognitive impairment 31, neuronal migrational defects 32, bipolar disorder 33 and endometrial stromal sarcoma 34.…”