Ursodeoxycholic Acid Improves Mitochondrial Function and Redistributes Drp1 in Fibroblasts from Patients with Either Sporadic or Familial Alzheimer's Disease

Bell, Simon M; Barnes, Katy; Clemmens, Hannah; Alrafiah, Aziza; Al-ofi, Ebtisam A.; Leech, Vicki; Bandmann, Oliver; Shaw, Pamela J.; Blackburn, Daniel; Ferraiuolo, Laura; Mortiboys, Heather

doi:10.1016/j.jmb.2018.08.019

Cited by 64 publications

(68 citation statements)

References 39 publications

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“…We observed ursodiol to decrease oxidative stress and increase mitochondrial membrane potential, under stressed and non-stressed conditions, and improve cell viability in VWMD astrocytes under proteasomal stress. The increase of mitochondrial membrane potential by ursodiol identi ed in our study is consistent with reports for Alzheimer's disease patient broblasts (46). Considering disrupted mitochondrial function has been extensively implicated in VWMD and a wide range of neurodegenerative disorders, further investigation of the neuroprotective effects of ursodiol are warranted.…”

Section: Discussionsupporting

confidence: 92%

“…Patient-derived cells are a useful resource to support drug repurposing studies for rare diseases. Together with information from previous studies on other CNS diseases (42,46) our preliminary ndings are supportive toward ongoing in vivo investigation of ursodiol, zileuton and other anti-in ammatory drugs as cytoprotective agents for VWMD. Effect of candidate drugs on ISR markers in vehicle control (blue circle) or 0.1 µM MG132-treated (orange triangle) VWMD1 EIF2B5R113H/A403V patient iPSC-derived astrocytes.…”

Section: Resultssupporting

confidence: 82%

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Identification of Repurposable Cytoprotective Drugs in Vanishing White Matter Disease Patient-Derived cells

Cabral-da-Silva

Maksour

et al. 2020

Preprint

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BackgroundVanishing white matter disease (VWMD) is a rare leukodystrophy caused by mutations of the guanine exchange factor eIF2B that typically presents with juvenile onset. There are few treatments and no cures for the disease. Recent progress in the field has established mitochondrial dysfunction and endoplasmic reticulum (ER) stress to be strongly implicated in observed glial cell pathology. Drug repurposing offers a rapid approach toward translation of therapeutics with already-licensed drugs. ObjectiveThe aim of this study was to use fibroblasts and induced pluripotent stem cell (iPSC)-derived astrocytes from patients bearing the EIF2B5R113H/A403V or EIF2B2G200V/E213G VWMD mutations to identify potentially repurposable FDA-approved drugs based on in vitro assays. MethodsCell viability in the presence or absence of stress was assessed by resazurin reduction activity assay, mitochondrial membrane potential by TMRE fluorescence, and oxidative stress by H2DCFDA oxidation. Relative eIF2B phosphorylation, GADD34 and CHOP were quantified by fluorescent western blot. ResultsDysregulated GADD34 and CHOP were identified in patient fibroblasts and iPSC-derived astrocytes under induced stress conditions. A drug screen from a 2,400 FDA-approved drug library with EIF2B5R113H/A403V VWMD patient fibroblasts identified 113 anti-inflammatory drugs as a major class of hits with cytoprotective effects. A panel of potential candidate drugs, including berberine, deflazacort, ursodiol, zileuton, guanabenz and Anavex 2-73, and preclinical ISRIB, increased cell survival of EIF2B5R113H/A403V or EIF2B2G200V/E213G VWMD astrocytes, and were further investigated for their effect on the integrated stress response and mitochondrial stress. Ursodiol demonstrated capacity to ameliorate oxidative stress and loss of mitochondrial membrane potential in VWMD patient iPSC-derived astrocytes in the presence or absence of stress conditions. ConclusionPatient-derived cells can be used to identify cellular phenotypes and for large-scale drug screening. Anti-inflammatory compounds, such as berberine, deflazacort, ursodiol and zileuton are potentially repurposable drug candidates for VWMD that should be further investigated for translation in vivo.

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Section: Discussionsupporting

confidence: 92%

Section: Resultssupporting

confidence: 82%

Identification of Repurposable Cytoprotective Drugs in Vanishing White Matter Disease Patient-Derived cells

Cabral-da-Silva

Maksour

et al. 2020

Preprint

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“…6.1 | Drp1 and AD AD, the most common neurodegenerative disorders all over the world, is a progressive and age-dependent disease characterized by the long-term memory and cognitive function decline and changes in the patient personality and behavior. Currently, more than 36 million people older than 65-years old all over the world were diagnosed as having AD, causing it becomes a huge healthy concern in the society (Baek et al, 2017;Bell et al, 2018 (Filichia, Hoffer, Qi, & Luo, 2016;Rahimmi, Khosrobakhsh, Izadpanah, Moloudi, & Hassanzadeh, 2015;Rappold et al, 2014;Z. Zhang, Liu, Jiang, Zhai, & Xing, 2016;Zuo et al, 2014).…”

mentioning

confidence: 99%

Dynamin‐related protein 1: A critical protein in the pathogenesis of neural system dysfunctions and neurodegenerative diseases

Huang

Xie

et al. 2018

Journal Cellular Physiology

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Mitochondria play a key role in the maintenance of neuronal function by continuously providing energy. Here, we will give a detailed review about the recent developments in regards to dynamin‐related protein 1 (Drp1) induced unbalanced mitochondrial dynamics, excessive mitochondrial division, and neuronal injury in neural system dysfunctions and neurodegenerative diseases, including the Drp1 knockout induced mice embryonic death, the dysfunction of the Drp1‐dependent mitochondrial division induced neuronal cell apoptosis and impaired neuronal axonal transportation, the abnormal interaction between Drp1 and amyloid β (Aβ) in Alzheimer's disease (AD), the mutant Huntingtin (Htt) in Huntington's disease (HD), and the Drp1‐associated pathogenesis of other neurodegenerative diseases such as Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS). Drp1 is required for mitochondrial division determining the size, shape, distribution, and remodeling as well as maintaining of mitochondrial integrity in mammalian cells. In addition, increasing reports indicate that the Drp1 is involved in some cellular events of neuronal cells causing some neural system dysfunctions and neurodegenerative diseases, including impaired mitochondrial dynamics, apoptosis, and several posttranslational modification induced increased mitochondrial divisions. Recent studies also revealed that the Drp1 can interact with Aβ, phosphorylated τ, and mutant Htt affecting the mitochondrial shape, size, distribution, axonal transportation, and energy production in the AD and HD neuronal cells. These changes can affect the health of mitochondria and the function of synapses causing neuronal injury and eventually leading to the dysfunction of memory, cognitive impairment, resting tremor, posture instability, involuntary movements, and progressive muscle atrophy and paralysis in patients.

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“…Patient-derived cells are a useful resource to support drug repurposing studies for rare diseases. Together with information from previous studies on other CNS diseases (42,46) stress on protein expression of the ISR markers, p-eIF2α (normalised to eIF2α), GADD34 or CHOP, at 0, 24 or 48 h incubation period. Protein levels were quanti ed by western blot, normalised to total protein, and are shown relative to control at time 0.…”

Section: Resultsmentioning

confidence: 93%

Identification of repurposable cytoprotective drugs in Vanishing White Matter Disease patient-derived cells

Cabral-da-Silva

Maksour

et al. 2020

Preprint

View full text Add to dashboard Cite

Background Vanishing white matter disease (VWMD) is a rare leukodystrophy caused by mutations of the guanine exchange factor eIF2B that typically presents with juvenile onset. There are few treatments and no cures for the disease. Recent progress in the field has established mitochondrial dysfunction and endoplasmic reticulum (ER) stress to be strongly implicated in observed glial cell pathology. Drug repurposing offers a rapid approach toward translation of therapeutics with already-licensed drugs. Objective The aim of this study was to use fibroblasts and induced pluripotent stem cell (iPSC)-derived astrocytes from patients bearing the EIF2B5R113H/A403V or EIF2B2G200V/E213G VWMD mutations to identify potentially repurposable FDA-approved drugs based on in vitro assays. Methods Cell viability in the presence or absence of stress was assessed by resazurin reduction activity assay, mitochondrial membrane potential by TMRE fluorescence, and oxidative stress by H2DCFDA oxidation. Relative eIF2B phosphorylation, GADD34 and CHOP were quantified by fluorescent western blot. Results Dysregulated GADD34 and CHOP were identified in patient fibroblasts and iPSC-derived astrocytes under induced stress conditions. A drug screen from a 2,400 FDA-approved drug library with EIF2B5R113H/A403V VWMD patient fibroblasts identified 113 anti-inflammatory drugs as a major class of hits with cytoprotective effects. A panel of potential candidate drugs, including berberine, deflazacort, ursodiol, zileuton, guanabenz and Anavex 2–73, and preclinical ISRIB, increased cell survival of EIF2B5R113H/A403V or EIF2B2G200V/E213G VWMD astrocytes, and were further investigated for their effect on the integrated stress response and mitochondrial stress. Ursodiol demonstrated capacity to ameliorate oxidative stress and loss of mitochondrial membrane potential in VWMD patient iPSC-derived astrocytes in the presence or absence of stress conditions. Conclusion Patient-derived cells can be used to identify cellular phenotypes and for large-scale drug screening. Anti-inflammatory compounds, such as berberine, deflazacort, ursodiol and zileuton are potentially repurposable drug candidates for VWMD that should be further investigated for translation in vivo.

show abstract

Ursodeoxycholic Acid Improves Mitochondrial Function and Redistributes Drp1 in Fibroblasts from Patients with Either Sporadic or Familial Alzheimer's Disease

Cited by 64 publications

References 39 publications

Identification of Repurposable Cytoprotective Drugs in Vanishing White Matter Disease Patient-Derived cells

Identification of Repurposable Cytoprotective Drugs in Vanishing White Matter Disease Patient-Derived cells

Dynamin‐related protein 1: A critical protein in the pathogenesis of neural system dysfunctions and neurodegenerative diseases

Identification of repurposable cytoprotective drugs in Vanishing White Matter Disease patient-derived cells

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