PINCH in the Cellular Stress Response to Tau-Hyperphosphorylation

Abstract

Particularly interesting new cysteine- histidine- rich protein (PINCH) is an adaptor protein that our data have shown is required for neurite extension under stressful conditions. Our previous studies also report that PINCH is recalled by neurons showing decreased levels of synaptodendritic signaling proteins such as MAP2 or synaptophysin in the brains of human immunodeficiency virus (HIV) patients. The current study addressed potential role(s) for PINCH in neurodegenerative diseases. Mass spectrometry predicted the interaction of PINCH with Tau and with members of the heat shock response. Our in vitro data confirmed that PINCH binds to hyperphosphorylated (hp) Tau and to E3 ubiquitin ligase, carboxy-terminus of heat shock-70 interacting protein. Silencing PINCH prior to induction of hp-Tau resulted in more efficient clearance of accumulating hp-Tau, suggesting that PINCH may play a role in stabilizing hp-Tau. Accumulation of hp-Tau is implicated in more than 20 neuropathological diseases including Alzheimer's disease (AD), frontotemporal dementia (FTD), and human immunodeficiency virus encephalitis (HIVE). Analyses of brain tissues from HIVE, AD and FTD patients showed that PINCH is increased and binds to hp-Tau. These studies address a new mechanism by which AD and HIV may intersect and identify PINCH as a contributing factor to the accumulation of hyperphosphorylated Tau.

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].…”

“…Our results suggest that changes in CSF levels of PINCH correlate with CSF hpTau levels in this cohort of HIV participants. Previous studies reported that PINCH and hpTau bind one another both in vitro , in vivo and in the brains and CSF of HIV patients [6]. Our earlier studies also reported higher levels of PINCH in brain and CSF in both HIV with no CNS alterations and HIVE, compared to HIV negative adults.…”

“…Likewise, PINCH binds to and inactivates protein phosphatase 1 α (PP1α) that is involved in the dephosphorylation of Tau residues essential for normal Tau-microtubule interactions [41]. The heat shock response represents a third potential pathway that may contribute to PINCH/hpTau interactions, as we have shown that PINCH binds to both hpTau and to the E3 ubiquitin ligase (CHIP) [6]. In this context, knockdown of PINCH in neurons where hpTau was induced resulted in less hpTau detection, which could be a result of less formation of hpTau, more efficient clearance, or both.…”

“…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].…”

“…Accumulation of hyperphosphorylated Tau (hpTau) is a common pathological feature of AD and is reported in HIV, as well [6, 10, 11]. In this context, our recent data show that PINCH binds to hpTau in HIV and AD patients' brains and loses solubility along with hpTau [6]. Moreover, we have shown that the HIV protein Tat and the chemokine TNF-α induce both PINCH expression and hpTau in human primary neurons in vitro [5].…”