Dual Vulnerability of TDP-43 to Calpain and Caspase-3 Proteolysis after Neurotoxic Conditions and Traumatic Brain Injury

Abstract

Transactivation response DNA-binding protein 43 (TDP-43) proteinopathy has recently been reported in chronic traumatic encephalopathy, a neurodegenerative condition linked to prior history of traumatic brain injury (TBI). While TDP-43 appears to be vulnerable to proteolytic modifications under neurodegenerative conditions, the mechanism underlying the contribution of TDP-43 to the pathogenesis of TBI remains unknown. In this study, we first mapped out the calpain or caspase-3 TDP-43 fragmentation patterns by in vitro protease digestion. Concurrently, in cultured cerebrocortical neurons subjected to cell death challenges, we identified distinct TDP-43 breakdown products (BDPs) of 35, 33, and 12 kDa that were indicative of dual calpain/caspase attack. Cerebrocortical culture incubated with calpain and caspase-fragmented TDP-43 resulted in neuronal injury. Furthermore, increased TDP-43 BDPs as well as redistributed TDP-43 from the nucleus to the cytoplasm were observed in the mouse cortex in two TBI models: controlled cortical impact injury and overpressure blast-wave-induced brain injury. Finally, TDP-43 and its 35 kDa fragment levels were also elevated in the cerebrospinal fluid (CSF) of severe TBI patients. This is the first evidence that TDP-43 might be involved in acute neuroinjury and TBI pathology, and that TDP-43 and its fragments may have biomarker utilities in TBI patients.

Traumatic brain injury causes frontotemporal dementia and TDP-43 proteolysis

“…TBI is a major risk factor for developing dementia, and increased levels of soluble amyloid b peptide and deposition of amyloid plaques explain the occurrence of dementia (Rosso et al, 2003;Loane et al, 2009;DeKosky et al, 2010;Querfurth and LaFerla, 2010;Rossor et al, 2010;Tran et al, 2011;Wang et al, 2012a,b). However, the amyloid hypothesis cannot explain why TDP-43 proteolysis occurs in patients with a single episode of TBI and chronic traumatic encephalopathy (McKee et al, 2010;Yang et al, 2014). Furthermore, TDP-43 inclusions are considered as neuropathological hallmarks of FTD (Seelaar et al, 2011;Sieben et al, 2012).…”

“…Unfortunately, motor neuron diseases often exhibit ubiquitin-and TDP-43-immunoreactive inclusion bodies, making it difficult to determine whether TDP-43 proteinopathy is caused by head injury. Yang et al showed that protease-generated TDP-43 fragments may gain neurotoxic function and induce secondary injury, and that TDP-43 and its fragments may have biomarker utilities in TBI patients (Yang et al, 2014). However, in another study by Johnson et al that aggregates of TDP-43 were not increased acutely or long-term following TBI (Johnson et al, 2011).…”

“…Patients with single TBI and chronic traumatic encephalopathy have TDP-43 proteinopathy (McKee et al, 2010;Yang et al, 2014). McKee et al showed that repetitive head injury is associated with TDP-43 proteinopathy and motor neuron disease development (McKee et al, 2010).…”

Plasma Anti-Glial Fibrillary Acidic Protein Autoantibody Levels during the Acute and Chronic Phases of Traumatic Brain Injury: A Transforming Research and Clinical Knowledge in Traumatic Brain Injury Pilot Study

“…26,39 While the number of plasma samples is still relatively small within the cohort, the TRACK-TBI pilot dataset was selected for this study because it is well-characterized with 13 published articles regarding various components of these TBI patients across the full range of TBI severity-including proteomic and genetic biomarkers, neuroimaging, and outcome data. 31,36,37,[40][41][42][43] Based on the 217 subjects with available biosamples from this cohort, we identified that anti-GFAP autoantibody levels were elevated in acute plasma samples from brain injury subjects who had a self-reported history of previous TBI with or without LOC when compared with patients with acute TBI without self-reported previous TBI (Fig.…”

O5‐06‐01: TDP‐43 Suppresses TAU Expression VIA Promoting its Mrna Instability

“…In the present study, we found that various deletion mutations of TDP-43 lost its ability to suppress the expression of tau. Thus, cleavage of TDP-43 due to activation of calpain (67,75) and AEP (68) caused by traumatic brain injury may contribute to tau pathology in CTE.…”