Novel expression of PINCH in the central nervous system and its potential as a biomarker for human immunodeficiency virus‐associated neurodegeneration

Abstract

Particularly interesting cysteine histidine-rich (PINCH) protein functions as a shuttling protein in Schwann cells after peripheral nerve damage, during repair and remodeling, and in maintaining neuronal polarity. However, the presence of PINCH in the human CNS during disease has not been addressed. Because HIV-associated damage to cells of the CNS involves dysregulation of neuronal signaling and white matter damage, we hypothesized that PINCH may play a role in neuropathological processes during the course of HIV infection. To determine the expression of PINCH in the CNS, brain, and cerebrospinal fluid (CSF) obtained at autopsy from HIV patients with no CNS alterations, HIV encephalitic (HIVE) patients, and HIV-negative individuals with no CNS alterations were examined for PINCH immunoreactivity. Our results show that PINCH is expressed robustly in the brains and CSF of HIV patients, but is nearly undetectable in HIV-negative individuals. However, HIVE patients' CSF contained significantly less PINCH than HIV patients with no CNS alterations. PINCH immunolabeling was significantly more intense in the white matter than in the grey matter and was associated exclusively with neuronal cell bodies or processes, or with the extracellular matrix. Given the recently discovered importance of PINCH in maintaining neuronal fitness, our observations that PINCH is robustly expressed in the CNS of HIV patients suggests an important role for PINCH in HIV-associated neurodegenerative processes. Understanding mechanisms by which PINCH functions during HIV-associated CNS alterations will provide new insight into potential treatments to limit neurological alterations in HIV.

Changes in PINCH levels in the CSF of HIV+ individuals correlate with hpTau and CD4 count

“…Distinct PINCH bands were detected at approximately 55 and 71 kDa (Figure 1A), as previously reported [4, 6]. A third PINCH immunoreactive band was detected at approximately 84 kDa in some cases, reminiscent of the approximate size detected by immunoprecipitation of PINCH and hpTau [6].…”

“…Moreover, our data show that increased CSF levels of PINCH correspond with a more favorable immune response as defined by improved CD4 count. Previous data reported that increased PINCH is observed in the brains and CSF of HIV patients, but it was also shown that patients with HIVE had more PINCH in their brains compared to CSF [4]. Likewise, HIV patients with no CNS alterations had less PINCH in the brain and more in the CSF.…”

“…Particularly interesting new cysteine histidine rich protein (PINCH), is an adaptor protein involved in cytoskeletal organization, cell attachment and survival [1-3], and is suggested to play an important role in neurodegenerative diseases including human immunodeficiency virus encephalitis (HIVE) and Alzheimer's Disease (AD) [4-6]. PINCH1 protein consists of 5 LIM domains and has no known catalytic activity [1, 2, 7].…”

“…While PINCH is expressed at high levels during development and in disease, in healthy patients, PINCH is nearly undetectable. In the brain, PINCH is upregulated in dystrophic neurons and is also present in brain parenchyma with no apparent association with cellular components [4, 5]. …”

“…Hence, longitudinal studies and clinical trials exploring biomarkers to examine the relationship between immune system and HIV are essential to effectively evaluate age-related disease CNS progression and treatment efficacy in HIV patients. Earlier studies report that although PINCH CSF levels are significantly elevated in all HIV patients, CSF levels of PINCH are significantly higher in HIV patients without encephalitis compared to those with HIVE [35], suggesting that changes in PINCH CSF levels may relate, in part to inflammatory status of the brain.…”