Mitochondrial dysfunction in neurodegenerative diseases: A focus on iPSC-derived neuronal models

Trombetta-Lima, Marina; Sabogal‐Guáqueta, Angélica Maria; Dolga, Amalia M.

doi:10.1016/j.ceca.2021.102362

Cited by 33 publications

(12 citation statements)

References 151 publications

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“…Although cell-cell interactions are dysregulated in AD brain (Henstridge et al, 2019), this feature of AD is often overlooked in in vitro studies. The brain-on-a-chip platform using induced pluripotent stem cells (iPSCs) -derived neurons and glia from AD patients could allow a high throughput screening of the effect of anti-ferroptotic drugs in AD, while mimicking the cellcell interactions in AD context (Trombetta-Lima et al, 2021). Moreover, this model is easily reproducible and thanks to the use of iPSCs from AD patients, also more translatable to humans compared to well-established animal models.…”

Section: Discussionmentioning

confidence: 99%

The Potential of Ferroptosis-Targeting Therapies for Alzheimer’s Disease: From Mechanism to Transcriptomic Analysis

Majerníková

Dunnen

Dolga

2021

Front. Aging Neurosci.

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Alzheimer’s disease (AD), the most common form of dementia, currently affects 40–50 million people worldwide. Despite the extensive research into amyloid β (Aβ) deposition and tau protein hyperphosphorylation (p-tau), an effective treatment to stop or slow down the progression of neurodegeneration is missing. Emerging evidence suggests that ferroptosis, an iron-dependent and lipid peroxidation-driven type of programmed cell death, contributes to neurodegeneration in AD. Therefore, how to intervene against ferroptosis in the context of AD has become one of the questions addressed by studies aiming to develop novel therapeutic strategies. However, the underlying molecular mechanism of ferroptosis in AD, when ferroptosis occurs in the disease course, and which ferroptosis-related genes are differentially expressed in AD remains to be established. In this review, we summarize the current knowledge on cell mechanisms involved in ferroptosis, we discuss how these processes relate to AD, and we analyze which ferroptosis-related genes are differentially expressed in AD brain dependant on cell type, disease progression and gender. In addition, we point out the existing targets for therapeutic options to prevent ferroptosis in AD. Future studies should focus on developing new tools able to demonstrate where and when cells undergo ferroptosis in AD brain and build more translatable AD models for identifying anti-ferroptotic agents able to slow down neurodegeneration.

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Section: Discussionmentioning

confidence: 99%

The Potential of Ferroptosis-Targeting Therapies for Alzheimer’s Disease: From Mechanism to Transcriptomic Analysis

Majerníková

Dunnen

Dolga

2021

Front. Aging Neurosci.

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“…Mitophagy is impaired in many neurodegenerative diseases, leading to accumulation of defective mitochondria. Hence, human iPSC-derived neuronal models have greatly contributed to the study of mitophagic clearance in the pathogenesis of PD [ 152 ]. Several studies, outlined below, demonstrate impaired mitophagic flux in human iPSC-derived dopaminergic neurons carrying PD-related PINK1 and Parkin mutations.…”

Section: Discoveries Of Mitochondria-specific Phenotypes In Ipsc Models Of Pdmentioning

confidence: 99%

Mitochondrial Phenotypes in Parkinson’s Diseases—A Focus on Human iPSC-Derived Dopaminergic Neurons

Heger

Wise

Hees

et al. 2021

Cells

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Established disease models have helped unravel the mechanistic underpinnings of pathological phenotypes in Parkinson’s disease (PD), the second most common neurodegenerative disorder. However, these discoveries have been limited to relatively simple cellular systems and animal models, which typically manifest with incomplete or imperfect recapitulation of disease phenotypes. The advent of induced pluripotent stem cells (iPSCs) has provided a powerful scientific tool for investigating the underlying molecular mechanisms of both familial and sporadic PD within disease-relevant cell types and patient-specific genetic backgrounds. Overwhelming evidence supports mitochondrial dysfunction as a central feature in PD pathophysiology, and iPSC-based neuronal models have expanded our understanding of mitochondrial dynamics in the development and progression of this devastating disorder. The present review provides a comprehensive assessment of mitochondrial phenotypes reported in iPSC-derived neurons generated from PD patients’ somatic cells, with an emphasis on the role of mitochondrial respiration, morphology, and trafficking, as well as mitophagy and calcium handling in health and disease. Furthermore, we summarize the distinguishing characteristics of vulnerable midbrain dopaminergic neurons in PD and report the unique advantages and challenges of iPSC disease modeling at present, and for future mechanistic and therapeutic applications.

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“…Indeed, patient-derived iPSC models have been generated and validated, especially for their capacity to progressively express the primary pathological markers, such as aggregation of Aβ, tau hyperphosphorylation, and α-synuclein misfolding, which are typical hallmarks observed in tissues from AD and PD patients [214][215][216]. Importantly, sAD-derived neurons or non-AD-derived neurons treated with Aβ present standard features like mtDNA damage, mitochondrial dysfunction, and increased ROS production [217].…”

Section: Ipscsmentioning

confidence: 99%

The use of fibroblasts as a valuable strategy for studying mitochondrial impairment in neurological disorders

Olesen

Villavicencio-Tejo

Quintanilla

2022

Transl Neurodegener

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Neurological disorders (NDs) are characterized by progressive neuronal dysfunction leading to synaptic failure, cognitive impairment, and motor injury. Among these diseases, Alzheimer's disease (AD), Parkinson's disease (PD), Huntington’s disease (HD), and amyotrophic lateral sclerosis (ALS) have raised a significant research interest. These disorders present common neuropathological signs, including neuronal dysfunction, protein accumulation, oxidative damage, and mitochondrial abnormalities. In this context, mitochondrial impairment is characterized by a deficiency in ATP production, excessive production of reactive oxygen species, calcium dysregulation, mitochondrial transport failure, and mitochondrial dynamics deficiencies. These defects in mitochondrial health could compromise the synaptic process, leading to early cognitive dysfunction observed in these NDs. Interestingly, skin fibroblasts from AD, PD, HD, and ALS patients have been suggested as a useful strategy to investigate and detect early mitochondrial abnormalities in these NDs. In this context, fibroblasts are considered a viable model for studying neurodegenerative changes due to their metabolic and biochemical relationships with neurons. Also, studies of our group and others have shown impairment of mitochondrial bioenergetics in fibroblasts from patients diagnosed with sporadic and genetic forms of AD, PD, HD, and ALS. Interestingly, these mitochondrial abnormalities have been observed in the brain tissues of patients suffering from the same pathologies. Therefore, fibroblasts represent a novel strategy to study the genesis and progression of mitochondrial dysfunction in AD, PD, HD, and ALS. This review discusses recent evidence that proposes fibroblasts as a potential target to study mitochondrial bioenergetics impairment in neurological disorders and consequently to search for new biomarkers of neurodegeneration.

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Mitochondrial dysfunction in neurodegenerative diseases: A focus on iPSC-derived neuronal models

Cited by 33 publications

References 151 publications

The Potential of Ferroptosis-Targeting Therapies for Alzheimer’s Disease: From Mechanism to Transcriptomic Analysis

The Potential of Ferroptosis-Targeting Therapies for Alzheimer’s Disease: From Mechanism to Transcriptomic Analysis

Mitochondrial Phenotypes in Parkinson’s Diseases—A Focus on Human iPSC-Derived Dopaminergic Neurons

The use of fibroblasts as a valuable strategy for studying mitochondrial impairment in neurological disorders

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