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      Role of UCHL1 in axonal injury and functional recovery after cerebral ischemia

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          Significance

          Many neuroprotective strategies have failed to translate to clinical trials, perhaps because of a failure to preserve white matter function. Ubiquitin C-terminal hydrolase L1 (UCHL1), a neuron-specific protein essential for axonal function, is deactivated by reactive lipids produced after cerebral ischemia. Mutation of the cysteine residue 152-reactive lipid-binding site of UCHL1 decreased axonal injury after hypoxia and ischemia in vitro and in vivo, preserved axonal conductance and synaptic function, and improved motor behavior after ischemia in mice. These results suggest that UCHL1 may play an important role in maintaining axonal function after cerebral ischemia. Restoration of UCHL1 activity or prevention of degradation of UCHL1 activity by preventing binding of substrates to cysteine residue 152 could be useful approaches for treatment of stroke.

          Abstract

          Ubiquitin C-terminal hydrolase L1 (UCHL1) is a unique brain-specific deubiquitinating enzyme. Mutations in and aberrant function of UCHL1 have been linked to many neurological disorders. UCHL1 activity protects neurons from hypoxic injury, and binding of stroke-induced reactive lipid species to the cysteine 152 (C152) of UCHL1 unfolds the protein and disrupts its function. To investigate the role of UCHL1 and its adduction by reactive lipids in inhibiting repair and recovery of function following ischemic injury, a knock-in (KI) mouse expressing the UCHL1 C152A mutation was generated. Neurons derived from KI mice had less cell death and neurite injury after hypoxia. UCHL1 C152A KI and WT mice underwent middle cerebral artery occlusion (MCAO) or sham surgery. White matter injury was significantly decreased in KI compared with WT mice 7 d after MCAO. Histological analysis revealed decreased tissue loss at 21 d after injury in KI mice. There was also significantly improved sensorimotor recovery in postischemic KI mice. K63- and K48-linked polyubiquitinated proteins were increased in penumbra of WT mouse brains but not in KI mouse brains at 24 h post MCAO. The UCHL1 C152A mutation preserved excitatory synaptic drive to pyramidal neurons and their excitability in the periinfarct zone; axonal conduction velocity recovered by 21 d post MCAO in KI mice in corpus callosum. These results demonstrate that UCHL1 activity is an important determinant of function after ischemia and further demonstrate that the C152 site of UCHL1 plays a significant role in functional recovery after stroke.

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          Most cited references58

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          Nonproteolytic functions of ubiquitin in cell signaling.

          The small protein ubiquitin is a central regulator of a cell's life and death. Ubiquitin is best known for targeting protein destruction by the 26S proteasome. In the past few years, however, nonproteolytic functions of ubiquitin have been uncovered at a rapid pace. These functions include membrane trafficking, protein kinase activation, DNA repair, and chromatin dynamics. A common mechanism underlying these functions is that ubiquitin, or polyubiquitin chains, serves as a signal to recruit proteins harboring ubiquitin-binding domains, thereby bringing together ubiquitinated proteins and ubiquitin receptors to execute specific biological functions. Recent advances in understanding ubiquitination in protein kinase activation and DNA repair are discussed to illustrate the nonproteolytic functions of ubiquitin in cell signaling.
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            CNS plasticity and assessment of forelimb sensorimotor outcome in unilateral rat models of stroke, cortical ablation, parkinsonism and spinal cord injury.

            We have reviewed a battery of useful tests for evaluating sensorimotor function and plasticity acutely and chronically in unilateral rat models of central nervous system injury. These tests include forelimb use for weight shifting during vertical exploration in a cylindrical enclosure, an adhesive removal test of sensory function, and forelimb placing. These tests monitor recovery of sensorimotor function independent of the extent of test experience. Data are presented for four models, including permanent focal ischemia, focal injury to the forelimb area of sensorimotor cortex, dopaminergic neurodegeneration of the nigrostriatal system, and cervical spinal cord injury. The effect of the dendrite growth promoting factor, Osteogenic Protein-1 (OP-1) on outcome following permanent middle cerebral artery (MCA) occlusion was used as an example to illustrate how the tests can be applied preclinically. OP-1 showed a beneficial effect on limb use asymmetry in the cylinder test.
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              Repairing the human brain after stroke: I. Mechanisms of spontaneous recovery.

              Stroke remains a leading cause of adult disability. Some degree of spontaneous behavioral recovery is usually seen in the weeks after stroke onset. Variability in recovery is substantial across human patients. Some principles have emerged; for example, recovery occurs slowest in those destined to have less successful outcomes. Animal studies have extended these observations, providing insight into a broad range of underlying molecular and physiological events. Brain mapping studies in human patients have provided observations at the systems level that often parallel findings in animals. In general, the best outcomes are associated with the greatest return toward the normal state of brain functional organization. Reorganization of surviving central nervous system elements supports behavioral recovery, for example, through changes in interhemispheric lateralization, activity of association cortices linked to injured zones, and organization of cortical representational maps. A number of factors influence events supporting stroke recovery, such as demographics, behavioral experience, and perhaps genetics. Such measures gain importance when viewed as covariates in therapeutic trials of restorative agents that target stroke recovery.
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                Author and article information

                Journal
                Proc Natl Acad Sci U S A
                Proc. Natl. Acad. Sci. U.S.A
                pnas
                pnas
                PNAS
                Proceedings of the National Academy of Sciences of the United States of America
                National Academy of Sciences
                0027-8424
                1091-6490
                5 March 2019
                13 February 2019
                13 February 2019
                : 116
                : 10
                : 4643-4650
                Affiliations
                [1] aGeriatric Research Educational and Clinical Center, Veterans Affairs Pittsburgh Healthcare System , Pittsburgh, PA 15240;
                [2] bDepartment of Neurology, University of Pittsburgh School of Medicine , Pittsburgh, PA 15213;
                [3] cDepartment of Neuroscience, University of Pittsburgh , Pittsburgh, PA 15260
                Author notes
                2To whom correspondence may be addressed. Email: zhanfx2@ 123456upmc.edu or sgra@ 123456pitt.edu .

                Edited by Gregg L. Semenza, Johns Hopkins University School of Medicine, Baltimore, MD, and approved January 14, 2019 (received for review December 17, 2018)

                Author contributions: H.L., N.P., Z.M., G.B., F.Z., and S.H.G. designed research; H.L., N.P., M.E.R., Z.M., J.S.B., W.L., F.C., D.P.R., and F.Z. performed research; H.L., N.P., M.E.R., Z.M., F.Z., and S.H.G. analyzed data; and H.L., N.P., M.E.R., Z.M., F.Z., and S.H.G. wrote the paper.

                1H.L. and N.P. contributed equally to this work.

                Author information
                http://orcid.org/0000-0002-1718-2547
                Article
                201821282
                10.1073/pnas.1821282116
                6410860
                30760601
                5a4a2ad3-d854-4340-a12d-4d89d7aa7727
                Copyright © 2019 the Author(s). Published by PNAS.

                This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND).

                History
                Page count
                Pages: 8
                Funding
                Funded by: HHS | NIH | National Institute of Neurological Disorders and Stroke (NINDS) 100000065
                Award ID: 2R01NS037459-14A1
                Award Recipient : Hao Liu Award Recipient : Nadezhda V. Povysheva Award Recipient : Marie E Rose Award Recipient : Zhiping Mi Award Recipient : Joseph S Banton Award Recipient : Wenjin Li Award Recipient : Fenghua Chen Award Recipient : Daniel P. Reay Award Recipient : German Barrionuevo Award Recipient : Feng Zhang Award Recipient : Steven H. Graham
                Categories
                PNAS Plus
                Biological Sciences
                Neuroscience
                PNAS Plus

                uchl1,ischemia,axonal injury,electrophysiology,ubiquitin–proteasome pathway

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