Dysregulation of PINCH signaling in mesial temporal epilepsy

Abstract

Mounting evidence suggests that inflammation is important in epileptogenesis. Particularly Interesting New Cysteine Histidine-rich (PINCH) protein is a highly conserved, LIM-domain protein known to interact with hyperphosphorylated Tau. We assessed PINCH expression in resected epileptogenic human hippocampi and further explored the relationships among PINCH, hpTau and associated kinases. Resected hippocampal tissue from 7 patients with mesial temporal lobe epilepsy (MTLE) was assessed by Western analyses to measure levels of PINCH and hyperphosphorylated Tau, as well as changes in phosphorylation levels of associated kinases AKT and GSK3β in comparison to normal control tissue. Immunolabeling was also conducted to evaluate PINCH and hpTau patterns of expression, co-localization and cell-type specific expression. Hippocampal PINCH was increased by 2.6 fold in the epilepsy cases over controls and hpTau was increased 10 fold over control. Decreased phospho-AKT and phospho-GSK3β in epilepsy tissue suggested involvement of this pathway in MTLE. PINCH and hpTau co-localized in some neurons in MTLE tissue. While PINCH was expressed by both neurons and astrocytes in MTLE tissue, hpTau was extracellular or associated with neurons. PINCH was absent from the serum of control subjects but readily detectable from the serum of patients with chronic epilepsy. Our study describes the expression of PINCH and points to AKT/GSK3β signaling dysregulation as a possible pathway in hpTau formation in MTLE. In view of the interactions between hpTau and PINCH, understanding the role of PINCH in MTLE may provide increased understanding of mechanisms leading to inflammation and MTLE epileptogenesis and a potential biomarker for drug-resistant epilepsy.

Tau-Induced Pathology in Epilepsy and Dementia: Notions from Patients and Animal Models

“…Hyperphosphorylated tau aggregates have been observed in patients with epilepsy [ 72 , 73 , 74 , 75 , 76 ], as well as in different models of chemically and electrically generated epilepsy [ 77 , 78 , 79 , 80 ], although tau hyperphosphorylation is not always associated with seizures. Aggregates of hyperphosphorylated tau in the brain of patients with epilepsy were recognized by phospho-S396 [ 75 ], AT8 (against phospho-S202, -T205, -S199 and -S208 tau epitopes) [ 72 , 73 , 74 , 75 , 76 ] and AT100 (against phospho-S121 and -T214) [ 75 ] antibodies. In TLE, increased tau pathology has been related to epilepsy and cognitive decline [ 74 , 75 ].…”

Inflammation induced-PINCH expression leads to actin depolymerization and mitochondrial mislocalization in neurons

“…Likewise, in a tauopathy mouse model, PINCH was shown to be significantly increased in several brain regions, where it was undetectable in wildtype mice (18). Our findings were then expanded to AD, frontotemporal dementia and mesial temporal epilepsy patients' brains (17,18). Until recently, the overlap of increased PINCH and hpTau levels was unclear.…”

“…adult brains or in normal mature neurons. However, previous studies have reported a dramatic increase in PINCH expression brains from HIV, AD, epilepsy and CTE patients, and in neurons exposed to the HIV protein Tat or to TNF-α (16)(17)(18). Although expression of PINCH is observed in CNS disease, the regulatory mechanisms involved in PINCH expression are unknown.…”

“…shown that PINCH is nearly undetectable in healthy adult brain (16)(17)(18)(19). However, PINCH is robustly expressed in the brains of patients with neuroinflammatory or neurodegenerative disease with a tauopathy component including HIV (16,18,19), Alzheimer's disease (AD) (18), and epilepsy (17).…”

“…shown that PINCH is nearly undetectable in healthy adult brain (16)(17)(18)(19). However, PINCH is robustly expressed in the brains of patients with neuroinflammatory or neurodegenerative disease with a tauopathy component including HIV (16,18,19), Alzheimer's disease (AD) (18), and epilepsy (17). In vitro, PINCH is induced in neurons by exposure to TNFα directly, or indirectly by exposure to the HIV transactivator of transcription (Tat) protein that triggers TNFa production (16,18,(20)(21)(22).…”