Journal of neurochemistry
-
Journal of neurochemistry · Sep 2014
Therapeutic inducers of the HSP70/HSP110 protect mice against traumatic brain injury.
Traumatic brain injury (TBI) induces severe harm and disability in many accident victims and combat-related activities. The heat-shock proteins Hsp70/Hsp110 protect cells against death and ischemic damage. In this study, we used mice deficient in Hsp110 or Hsp70 to examine their potential requirement following TBI. ⋯ These studies indicate a significant role of Hsp70/Hsp110 in neuronal survival following TBI and the beneficial effects of Hsp70/Hsp110 inducers toward reducing the pathological consequences of TBI. Our data indicate that loss of Hsp110 or Hsp70 in mice increases brain injury following TBI. (a) One of the mechanisms underlying the increased cell death observed in the absence of these Hsps following TBI is the increased expression of ROS-induced p53 target genes known as Pigs. In addition, (b) using drugs (Celastrol or BGP-15) to increase Hsp70/Hsp110 levels protect cells against TBI, suggesting the beneficial effects of Hsp70/Hsp110 inducers to reduce the pathological consequences of TBI.
-
Journal of neurochemistry · Sep 2014
Endogenous neurotoxic dopamine derivative covalently binds to Parkinson's disease-associated ubiquitin C-terminal hydrolase L1 and alters its structure and function.
Parkinson's disease (PD) is a common neurodegenerative disease, but its pathogenesis remains elusive. A mutation in ubiquitin C-terminal hydrolase L1 (UCH-L1) is responsible for a form of genetic PD which strongly resembles the idiopathic PD. We previously showed that 1-(3',4'-dihydroxybenzyl)-1,2,3,4-tetrahydroisoquinoline (3',4'DHBnTIQ) is an endogenous parkinsonism-inducing dopamine derivative. ⋯ Our results indicate that 3',4'DHBnTIQ binds to UCH-L1 specifically at cysteine 152 and induces its aggregation. 3',4'DHBnTIQ also inhibits the hydrolase activity of UCH-L1. Catechol-modified as well as insoluble UCH-L1 were detected in the midbrains of MPTP-treated Parkinson's disease (PD) model mice. Conjugation of UCH-L1 by neurotoxic endogenous compounds like 3',4'DHBnTIQ might play a key role in onset and progression of PD.
-
Journal of neurochemistry · Jul 2014
Alterations in STriatal-Enriched protein tyrosine Phosphatase expression, activation, and downstream signaling in early and late stages of the YAC128 Huntington's disease mouse model.
Striatal neurodegeneration and synaptic dysfunction in Huntington's disease are mediated by the mutant huntingtin (mHtt) protein. MHtt disrupts calcium homeostasis and facilitates excitotoxicity, in part by altering NMDA receptor (NMDAR) trafficking and function. Pre-symptomatic (excitotoxin-sensitive) transgenic mice expressing full-length human mHtt with 128 polyglutamine repeats (YAC128 Huntington's disease mice) show increased calpain activity and extrasynaptic NMDAR (Ex-NMDAR) localization and signaling. ⋯ This study shows that elevated NMDA receptor-PSD-95 interactions as well as decreased extrasynaptic STriatal-Enriched protein tyrosine Phosphatase 61 (STEP61) activation may contribute to early enhanced apoptotic signaling. In late-stage YAC128 mice, reduced STEP61 levels and activity correlate with elevated MAPK signaling, consistent with excitotoxicity resistance. Solid and dotted arrows indicate conclusions drawn from the current study and other literature, respectively.
-
Journal of neurochemistry · Jun 2014
ReviewAnimal models of sports-related head injury: bridging the gap between pre-clinical research and clinical reality.
Sports-related head impact and injury has become a very highly contentious public health and medico-legal issue. Near-daily news accounts describe the travails of concussed athletes as they struggle with depression, sleep disorders, mood swings, and cognitive problems. Some of these individuals have developed chronic traumatic encephalopathy, a progressive and debilitating neurodegenerative disorder. ⋯ Animal models have always been an integral part of the study of human TBI but few existing methods are valid for studying SRHI. In this review, we propose criteria for effective animal models of SRHI. Movement of the head upon impact is judged to be of primary importance in leading to concussion and persistent CNS dysfunction.
-
Journal of neurochemistry · Jun 2014
Inhibition of striatal-enriched tyrosine phosphatase 61 in the dorsomedial striatum is sufficient to increased ethanol consumption.
The STriatal-Enriched protein tyrosine Phosphatase 61 (STEP61 ) inhibits the activity of the tyrosine kinase Fyn and dephosphorylates the GluN2B subunit of the NMDA receptor, whereas the protein kinase A phosphorylation of STEP61 inhibits the activity of the phosphatase (Pharmacol. Rev., 64, , p. 65). Previously, we found that ethanol activates Fyn in the dorsomedial striatum (DMS) leading to GluN2B phosphorylation, which, in turn, underlies the development of ethanol intake (J. ⋯ We show that ethanol-mediated inhibition of STEP61 in the DMS leads to Fyn activation and GluN2B phosphorylation. (a) Under basal conditions, active STEP61 inhibits Fyn activity and dephosphorylates GluN2B. (b) Ethanol leads to the phosphorylation of STEP61 on a specific inhibitory site. The inhibition of STEP61 activity contributes to the activation of Fyn in response to ethanol, which, in turn, phosphorylates GluN2B. These molecular adaptations in the DMS promote ethanol drinking.