In vivo transduction of neurons with TAT-UCH-L1 protects brain against controlled cortical impact injury

Líu, Hao; Rose, Marie E.; Ma, Xiecheng; Culver, Sherman; Dixon, C. Edward; Graham, Steven H.

doi:10.1371/journal.pone.0178049

Cited by 12 publications

(7 citation statements)

References 45 publications

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“…Mild TBI involves complex pathophysiologic processes associated with microscopic shearing of cells in the central nervous system secondary to traumatic biomechanical forces to the head (8). Such shearing induces damage to the cell, resulting in the release of neuronal and astrocytic proteins or cell-free DNA (cfDNA) not normally found in the extracellular space (9), including glial fibrillary acidic protein (GFAP) (10), ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1) (11), and Tau (12). Tau is a microtubule stabilizing protein abundant in neurons (13), and released into the extracellular space upon neuronal damage (14).…”

Section: Introductionmentioning

confidence: 99%

Plasma Biomarker for Post-concussive Syndrome: A Pilot Study Using an Alternating Current Electro-Kinetic Platform

et al. 2020

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Background: Technology platforms that afford biomarker discovery in patients suffering from traumatic brain injury (TBI) remain an unmet medical need. Here, we describe an observational pilot study to explore the utility of an alternating current electrokinetic (ACE) microchip device in this context. Methods: Blood samples were collected from participating subjects with and without minor TBI. Plasma levels of glial fibrillary acidic protein (GFAP), Tau, ubiquitin C-terminal hydrolase L1 (UCH-L1), and cell-free DNA (cfDNA) were determined in subjects with and without minor TBI using ACE microchip device followed by on-chip immunofluorescent analysis. Post-concussive symptoms were assessed using the Rivermead Post Concussion Symptoms Questionnaire (RPCSQ) at one-month follow-up. Results: Highest levels of GFAP, UCH-L1, and Tau were seen in two minor TBI subjects with abnormality on head computed tomography (CT). In patients without abnormal head CT, Tau and GFAP levels discriminated between plasma from minor-TBI and non-TBI patients, with sensitivity and specificity of 64-72 and 50%, respectively. Plasma GFAP, UCH-L1, and Tau strongly correlated with the cumulative RPCSQ score. Plasma UCH-L1 and GFAP exhibited highest correlation to sensitivity to noise and light (r = 0.96 and 0.91, respectively, p < 0.001). Plasma UCH-L1 and Tau showed highest correlation with headache (r = 0.74 and 0.78, respectively, p < 0.001), sleep disturbance (r = 0.69 and 0.84, respectively, p < 0.001), and cognitive symptoms, including forgetfulness (r = 0.76 and 0.74, respectively, p < 0.001), poor concentration (r = 0.68 and 0.76, respectively, p < 0.001), and time required for information processing (r = 0.77 and 0.81, respectively, p < 0.001). cfDNA exhibited a strong correlation with depression (r = 0.79, p < 0.01) and dizziness (r = 0.69, p < 0.01). While cfDNA demonstrated positive correlation with dizziness and depression (r = 0.69 and 0.79, respectively, p < 0.001), no significant correlation was observed between cumulative RPCSQ and cfDNA (r = 0.07, p = 0.81). Conclusion: We provide proof-of-principle results supporting the utility of ACE microchip for plasma biomarker analysis in patients with minor TBI.

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Section: Introductionmentioning

confidence: 99%

Plasma Biomarker for Post-concussive Syndrome: A Pilot Study Using an Alternating Current Electro-Kinetic Platform

et al. 2020

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“…UCHL1 protein fused to the protein transduction domain of HIV-transactivating transduction protein (TAT-UCHL1) can transduce neurons after intraperitoneal (i.p.) injection into mice [ 101 ]. In a controlled cortical impact (CCI) injury model of post-traumatic brain injury, TAT-UCHL1 treatment improved function of the ubiquitin-proteasome pathway, decreased activation of autophagy after CCI, attenuated axonal injury and increased hippocampal neuronal survival after CCI [ 101 ].…”

Section: Discussionmentioning

confidence: 99%

Upper motor neurons are a target for gene therapy and UCHL1 is necessary and sufficient to improve cellular integrity of diseased upper motor neurons

et al. 2021

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There are no effective cures for upper motor neuron (UMN) diseases, such as amyotrophic lateral sclerosis (ALS), primary lateral sclerosis, and hereditary spastic paraplegia. Here, we show UMN loss occurs independent of spinal motor neuron degeneration and that UMNs are indeed effective cellular targets for gene therapy, which offers a potential solution especially for UMN disease patients. UCHL1 (ubiquitin C-terminal hydrolase-L1) is a deubiquitinating enzyme crucial for maintaining free ubiquitin levels. Corticospinal motor neurons (CSMN, a.k.a UMNs in mice) show early, selective, and profound degeneration in Uchl1 nm3419 (UCHL1 −/− ) mice, which lack all UCHL1 function. When UCHL1 activity is ablated only from spinal motor neurons, CSMN remained intact. However, restoring UCHL1 specifically in CSMN of UCHL1 −/− mice via directed gene delivery, was sufficient to improve CSMN integrity to the healthy control levels. In addition, when UCHL1 gene was delivered selectively to CSMN that are diseased due to misfolded SOD1 toxicity and TDP-43 pathology via AAV-mediated retrograde transduction, the disease causing misfolded SOD1 and mutant human TDP-43 were reduced in hSOD1 G93A and prpTDP-43 A315T models, respectively. Diseased CSMN retained their neuronal integrity and cytoarchitectural stability in two different mouse models that represent two distinct causes of neurodegeneration in ALS.

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“…Previous work in rat models have shown that the concentration of UCH-L1 increases in the presence of brain damage (14), and the elevation in UCH-L1 levels reaches a peak at 6 hours after birth in brain-damaged human neonates (15). During HIE, brain injury results in the release of inflammatory factors, excessive production of free radicals, and other related phenomena, which interact with each other, leading to degeneration, necrosis, and apoptosis of brain neurons and the destruction of the blood-brain barrier (16)(17)(18). At this time, the brain releases a large amount of UCH-L1 protein which enters the blood through the damaged blood-brain barrier, and can thus be detected in the cerebrospinal fluid or blood during the acute stage of brain injury (19,20).…”

Section: Discussionmentioning

confidence: 99%

The expression and clinical value of ubiquitin carboxyl-terminal hydrolase L1 in the blood of neonates with hypoxic ischemic encephalopathy

Zeng¹,

Huang²,

Zhong³

et al. 2021

Transl Pediatr

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Background: Neonatal hypoxic ischemic encephalopathy (HIE) can result in mental retardation due to the associated brain damage. Early identification of brain injury is vital for the prevention and treatment of brain damage in neonates. This study investigated the expression levels of serum ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) in neonates with HIE and its correlation with brain damage.Methods: From January 2019 to December 2020, 56 cases of neonatal patients with HIE were selected as the observation group, and 60 cases of healthy newborns delivered in our hospital during the same period were selected as the control group. Blood samples were obtained from neonates and the serum expression of UCH-L1 was detected by enzyme-linked immunosorbent assays (ELISAs). The relationship between UCH-L1 and neonatal prognosis and clinical features was analyzed.Results: Compared with the healthy control group, the serum levels of UCH-L1 in the observation group was significantly higher (2.28±1.21 vs. 0.81±0.39 ng/mL, P=0.000). Furthermore, at 6 hours after birth, the serum levels of UCH-L1 were significantly higher in neonates with moderate to severe HIE compared to patients with mild HIE (2.92±0.80 and 1.76±0.72 ng/mL, respectively, P=0.000). Pearson correlation analysis showed that the expression levels of UCH-L1 were negatively correlated with the development quotient (DQ), intelligence index (MI), and the Neonatal Behavioral Neurological Assessment (NBNA) score of HIE newborns (P<0.05). Conclusions:The level of UCH-L1 protein expression is elevated in the serum of newborns with HIE, and this may have a certain clinical value in predicting the intelligence of children.

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In vivo transduction of neurons with TAT-UCH-L1 protects brain against controlled cortical impact injury

Cited by 12 publications

References 45 publications

Plasma Biomarker for Post-concussive Syndrome: A Pilot Study Using an Alternating Current Electro-Kinetic Platform

Plasma Biomarker for Post-concussive Syndrome: A Pilot Study Using an Alternating Current Electro-Kinetic Platform

Upper motor neurons are a target for gene therapy and UCHL1 is necessary and sufficient to improve cellular integrity of diseased upper motor neurons

The expression and clinical value of ubiquitin carboxyl-terminal hydrolase L1 in the blood of neonates with hypoxic ischemic encephalopathy

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