N-Terminal Truncated UCH-L1 Prevents Parkinson's Disease Associated Damage

Abstract

Ubiquitin C-terminal hydrolase-L1 (UCH-L1) has been proposed as one of the Parkinson's disease (PD) related genes, but the possible molecular connection between UCH-L1 and PD is not well understood. In this study, we discovered an N-terminal 11 amino acid truncated variant UCH-L1 that we called NT-UCH-L1, in mouse brain tissue as well as in NCI-H157 lung cancer and SH-SY5Y neuroblastoma cell lines. In vivo experiments and hydrogen-deuterium exchange (HDX) with tandem mass spectrometry (MS) studies showed that NT-UCH-L1 is readily aggregated and degraded, and has more flexible structure than UCH-L1. Post-translational modifications including monoubiquitination and disulfide crosslinking regulate the stability and cellular localization of NT-UCH-L1, as confirmed by mutational and proteomic studies. Stable expression of NT-UCH-L1 decreases cellular ROS levels and protects cells from H2O2, rotenone and CCCP-induced cell death. NT-UCH-L1-expressing transgenic mice are less susceptible to degeneration of nigrostriatal dopaminergic neurons seen in the MPTP mouse model of PD, in comparison to control animals. These results suggest that NT-UCH-L1 may have the potential to prevent neural damage in diseases like PD.

Life and death in the trash heap: The ubiquitin proteasome pathway and UCHL1 in brain aging, neurodegenerative disease and cerebral Ischemia

“…Furthermore, Kim et al recently discovered that over-expression of an N-terminal 11 amino acid truncated UCHL1 (NT-UCHL1) decreases cellular ROS levels and protects cells from H 2 O 2 - and rotenone- induced cell death. NT UCHL1-expressing transgenic mice are less susceptible to degeneration of nigrostriatal dopaminergic neurons seen in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD (Kim et al, 2014). …”

“…One approach is to replace UCHL1 activity in brain. The prothrombin domain of the HIV capsid protein trans-activator of transcription (TAT) confers the ability of HIV to readily enter neurons (Gong et al, 2006; Hill et al, 2012; Kim et al, 2014; Liu et al, 2011). By fusing the TAT with UCHL1, the resultant protein (TATUCHL1) readily enters neurons even when administered systemically.…”

“…Thus, TAT-UCHL1 treatment has the potential to be applied to patients with neurodegenerative diseases including AD and PD. Because UCHL1 may play an important role in axonal integrity and axonal transport, administration of TAT-UCHL1 could also be useful in other diseases where white matter and axonal function is important in recovery such as TBI and stroke (Gong et al, 2016; Kim et al, 2014). The identification of the C152 site as a critical binding site for reactive lipids provides a strategy for rational design of agents that would compete for binding of reactive lipids at this site.…”

Oxidative Stress and Parkinson’s Disease: Effects on Environmental Toxicology

“…Since the discovery that 1-methyl-4-phenyl-1,2,3,6-tetrahydrodropyridine infusion causes parkinsonism by selective inhibition of mitochondrial complex-1, raised the possibility that mitochondrial dysfunction is at the heart of PD [53].…”

“…In an experimental model, monomeric α-Syn-expressing dopaminergic cells significantly attenuated Mn-induced neurotoxicity for initial exposures. However, overexposure to Mn produces precipitation of α-syn, which at the same time impairs antioxidative defense mechanism in this experimental model [86][87][88].…”