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.
Highlights
Limited regenerative capacity in adults makes neurons in the human CNS vulnerable to stress
We have discovered that Interesting New Cysteine-Histidine-rich (PINCH) protein is upregulated in the neurons of patients with CNS disorders that have a Tau misfolding component, such as human immunodeficiency virus encephalitis (HIVE) and Alzheimer’s disease (AD)
Along with the expected hits, such as integrin linked kinase (ILK) and Nck-2, other top hits included microtubule-associated binding proteins and heat shock protein response (HSR)-related proteins that are involved in the clearance of abnormal cellular proteins
Summary
Limited regenerative capacity in adults makes neurons in the human CNS vulnerable to stress. Functions of the HSR include surveillance of proteins post-translationally and after cellular insult or stress. These stressors include diverse events such as chronic traumatic encephalopathy injury [1], Alzheimer’s disease (AD) [2], HIV encephalitis (HIVE) [3,4], and frontotemporal dementia (FTD) [5] and can manifest, in part, as accumulation of hyperphosphorylated Tau (hp-Tau). The heat shock protein 90 (Hsp90) has inherent ATPase activity, and studies suggest that Hsp may either 1) initiate the repair response for refolding and/or dephosphorylation, or 2) target clients including hp-Tau for UPS degradation by recruiting the E3 ubiquitin ligase, carboxy-terminus of heat shock-70 interacting protein (CHIP) [8]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
