ALS-causing SOD1 mutants regulate occludin phosphorylation/ubiquitination and endocytic trafficking via the ITCH/Eps15/Rab5 axis

Tang, Jingshu; Kang, Yuying; Zhou, Yujun; Li, Xinnan; Lan, Jiaqi; Wu, Lei; Xu, Feng; Peng, Ying

doi:10.1016/j.nbd.2021.105315

Cited by 8 publications

(3 citation statements)

References 51 publications

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“…Ultrastructural abnormalities accumulated over time in the BSCB of symptomatic SOD1 animal models as neuronal loss progressed (Garbuzova-Davis et al, 2007a ). Endothelial cells showed cytoplasmic disorganization, vacuolated mitochondria, and impaired basal membrane with reduced expression of tight junction proteins claudin-5, occludin, ZO-1 and proteoglycan agrin (Nicaise et al, 2009a ; Garbuzova-Davis et al, 2012 ; Meister et al, 2015 ; Ouali Alami et al, 2020 ; Tang et al, 2021 ).…”

Section: Resultsmentioning

confidence: 99%

Breached Barriers: A Scoping Review of Blood-Central Nervous System Barrier Pathology in Amyotrophic Lateral Sclerosis

Mirian

Moszczynski

Soleimani

et al. 2022

Front. Cell. Neurosci.

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IntroductionRecent studies have implicated changes in the blood-central nervous system barriers (BCNSB) in amyotrophic lateral sclerosis (ALS). The objective of this scoping review is to synthesize the current evidence for BCNSB structure and functional abnormalities in ALS studies and propose how BCNSB pathology may impact therapeutic development.MethodsA literature search was conducted using Ovid Medline, EMBASE, and Web of Science, from inception to November 2021 and limited to entries in English language. Simplified search strategy included the terms ALS/motor neuron disease and [BCNSB or blood-brain barrier (BBB) or blood-spinal cord barrier (BSCB)]. Henceforth, BCNSB is used as a term that is inclusive of the BBB and BSCB. Four independent reviewers conducted a title and abstract screening, hand-searched the reference lists of review papers, and performed a full text review of eligible studies. Included studies were original peer-reviewed full text publications, evaluating the structure and function of the BCNSB in preclinical models of ALS, clinical ALS, or postmortem human ALS tissue. There was no restriction on study design. The four reviewers independently extracted the data.ResultsThe search retrieved 2,221 non-duplicated articles and 48 original studies were included in the synthesis. There was evidence that the integrity of the BCNSB is disrupted throughout the course of the disease in rodent models, beginning prior to symptom onset and detectable neurodegeneration. Increased permeability, pharmacoresistance with upregulated efflux transporters, and morphological changes in the supporting cells of the BCNSB, including pericytes, astrocytes, and endothelial cells were observed in animal models. BCNSB abnormalities were also demonstrated in postmortem studies of ALS patients. Therapeutic interventions targeting BCNSB dysfunction were associated with improved motor neuron survival in animal models of ALS.ConclusionBCNSB structural and functional abnormalities are likely implicated in ALS pathophysiology and may occur upstream to neurodegeneration. Promising therapeutic strategies targeting BCNSB dysfunction have been tested in animals and can be translated into ALS clinical trials.

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Section: Resultsmentioning

confidence: 99%

Breached Barriers: A Scoping Review of Blood-Central Nervous System Barrier Pathology in Amyotrophic Lateral Sclerosis

Mirian

Moszczynski

Soleimani

et al. 2022

Front. Cell. Neurosci.

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“…Results found that mutant SOD1 induced occludin phosphorylation, which promoted the subsequent occludin ubiquitination mediated by the E3 ligase ITCH. Moreover, ubiquitinated occludin interacted with Eps15 to initiate its internalization, then trafficked to Rab5-positive vesicles, and be degraded by proteasomes, resulting in a reduction in cell surface localization and total abundance [79]. (3) Feng et al showed that the γ-secretase blocker DAPT reduced the permeability of the BBB by decreasing the ubiquitination and degradation of occludin during permanent brain ischemia [80].…”

Section: Occludin Ubiquitinationmentioning

confidence: 99%

The Role of Occludin in Vascular Endothelial Protection

Du¹,

Duan²,

Zhang³

2023

Endothelial Dysfunction - A Novel Paradigm

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Endothelial tight junction proteins play an important role in maintaining the integrity of vascular endothelial structure and physiological function. In recent years, studies have found that alterations in the expression, distribution, and structure of endothelial tight junction proteins may lead to many related vascular diseases and pathologies (such as diabetes, atherosclerosis, neurodegenerative diseases, and hypertension). Therefore, related strategies to prevent and/or tight junction proteins dysfunction may be an important therapeutic target. Occludin, as the most representative one among tight junction proteins, is mainly responsible for sealing intercellular junctions, maintaining cell permeability and the integrity of vascular endothelium. Here, we review the published biological information of occludin. We highlight the relationship between occludin and vascular endothelial injury-related disease. At the same time, we show our current knowledge of how vascular endothelial occludin exerts the protective effect and possible clinical applications in the future.

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“… 83 ROS promote phosphorylation and ubiquination of tight junction occludin proteins, marking them for degradation and weakening the BCNSB. 84 Like inflammation, oxidative stress may induce or be induced by BCNSB damage. Due to a weakened BSCB, hemoglobin and iron infiltration in the spinal cord amplify MN degeneration in ALS mice through oxidative stress.…”

Section: Als With Neurovascular Componentsmentioning

confidence: 99%

Patching Up the Permeability: The Role of Stem Cells in Lessening Neurovascular Damage in Amyotrophic Lateral Sclerosis

Monsour

Garbuzova‐Davis

Borlongan

2022

Stem Cells Translational Medicine

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Amyotrophic lateral sclerosis (ALS) is a debilitating disease with poor prognosis. The pathophysiology of ALS is commonly debated, with theories involving inflammation, glutamate excitotoxity, oxidative stress, mitochondria malfunction, neurofilament accumulation, inadequate nutrients or growth factors, and changes in glial support predominating. These underlying pathological mechanisms, however, act together to weaken the blood brain barrier and blood spinal cord barrier, collectively considered as the blood central nervous system barrier (BCNSB). Altering the impermeability of the BCNSB impairs the neurovascular unit, or interdependent relationship between the brain and advances the concept that ALS is has a significant neurovascular component contributing to its degenerative presentation. This unique categorization of ALS opens a variety of treatment options targeting the reestablishment of BCNSB integrity. This review will critically assess the evidence implicating the significant neurovascular components of ALS pathophysiology, while also offering an in-depth discussion regarding the use of stem cells to repair these pathological changes within the neurovascular unit.

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ALS-causing SOD1 mutants regulate occludin phosphorylation/ubiquitination and endocytic trafficking via the ITCH/Eps15/Rab5 axis

Cited by 8 publications

References 51 publications

Breached Barriers: A Scoping Review of Blood-Central Nervous System Barrier Pathology in Amyotrophic Lateral Sclerosis

Breached Barriers: A Scoping Review of Blood-Central Nervous System Barrier Pathology in Amyotrophic Lateral Sclerosis

The Role of Occludin in Vascular Endothelial Protection

Patching Up the Permeability: The Role of Stem Cells in Lessening Neurovascular Damage in Amyotrophic Lateral Sclerosis

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