Abolishing UCHL1's hydrolase activity exacerbates TBI-induced axonal injury and neuronal death in mice.

Abolishing UCHL1's hydrolase activity exacerbates TBI-induced axonal injury and neuronal death in mice.
Exp Neurol. 2020 Nov 04;:113524
Authors: Mi Z, Liu H, Rose ME, Ma X, Reay DP, Ma J, Henchir J, Dixon CE, Graham SH
Abstract
Ubiquitin (Ub) C-terminal hydrolase L1 (UCHL1) is a multifunctional protein that is expressed in neurons throughout brain at high levels. UCHL1 deletion is associated with axonal degeneration, progressive sensory motor ataxia, and premature death in mice. UCHL1 has been hypothesized to play a role in the pathogenesis of neurodegenerative diseases and recovery after neuronal injury. UCHL1 hydrolyzes Ub from polyubiquitinated (poly-Ub) proteins, but also may ligate Ub to select neuronal proteins, and interacts with cytoskeletal proteins. These and other mechanisms have been hypothesized to underlie UCHL1's role in neurodegeneration and response to brain injury. A UCHL1 knockin mouse containing a C90A mutation (C90A) devoid of hydrolase activity was constructed. The C90A mouse did not develop the sensory and motor deficits, degeneration of the gracile nucleus and tract, or premature death as seen in UCHL1 deficient mice. C90A and wild type (WT) mice were subjected to the controlled cortical impact (CCI) model of traumatic brain injury (TBI), and cell death, axonal injury and behavioral outcome were assessed. C90A mice exhibited decreased spared tissue volume, greater loss of CA1 hippocampal neurons and greater ax...

Source: Experimental Neurology - November 4, 2020 Category: Neurology Authors: Mi Z, Liu H, Rose ME, Ma X, Reay DP, Ma J, Henchir J, Dixon CE, Graham SH Tags: Exp Neurol Source Type: research