ALS skin fibroblasts reveal oxidative stress and ERK1/2-mediated cytoplasmic localization of TDP-43

Romano, Nicla; Catalani, Alessia; Lattante, Serena; Belardo, Antonio; Proietti, Sara; Bertini, Laura; Silvestri, Federica; Catalani, Elisabetta; Cervia, Davide; Zolla, Lello; Sabatelli, Mario; Welshhans, Kristy; Ceci, Marcello

doi:10.1016/j.cellsig.2020.109591

Cited by 21 publications

(23 citation statements)

References 60 publications

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“…Additionally, cytoplasmic localisation of TDP-43 has also been reported in human skin fibroblasts, resulting in specific molecular defects. 43 When combined with novel biomarkers, including assessment of disrupted cortical networks, 44 and measurement of neurofilament light chain, 45 as well as adoption of time-to-event trial endpoints, 46 the use of PBMCs and skin fibroblasts may provide unique research opportunities, especially in drug screening strategies.…”

Section: Mitochondrial Dysfunctionmentioning

confidence: 99%

TDP-43 proteinopathies: a new wave of neurodegenerative diseases

Boer

Orie

Williams³

et al. 2020

J Neurol Neurosurg Psychiatry

216

168

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Inclusions of pathogenic deposits containing TAR DNA-binding protein 43 (TDP-43) are evident in the brain and spinal cord of patients that present across a spectrum of neurodegenerative diseases. For instance, the majority of patients with sporadic amyotrophic lateral sclerosis (up to 97%) and a substantial proportion of patients with frontotemporal lobar degeneration (~45%) exhibit TDP-43 positive neuronal inclusions, suggesting a role for this protein in disease pathogenesis. In addition, TDP-43 inclusions are evident in familial ALS phenotypes linked to multiple gene mutations including the TDP-43 gene coding (TARDBP) and unrelated genes (eg, C9orf72). While TDP-43 is an essential RNA/DNA binding protein critical for RNA-related metabolism, determining the pathophysiological mechanisms through which TDP-43 mediates neurodegeneration appears complex, and unravelling these molecular processes seems critical for the development of effective therapies. This review highlights the key physiological functions of the TDP-43 protein, while considering an expanding spectrum of neurodegenerative diseases associated with pathogenic TDP-43 deposition, and dissecting key molecular pathways through which TDP-43 may mediate neurodegeneration.

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Section: Mitochondrial Dysfunctionmentioning

confidence: 99%

TDP-43 proteinopathies: a new wave of neurodegenerative diseases

Boer

Orie

Williams³

et al. 2020

J Neurol Neurosurg Psychiatry

216

168

View full text Add to dashboard Cite

show abstract

“…Increased oxidative stress is a key mechanism through which TDP-43 exerts mitochondrial damage, regulated by phosphorylation of extracellular signal-regulated kinases ERK1/2. In fibroblasts derived from patients with TARDBP mutations, abnormal metabolic activity and increases and indices of oxidative stress are associated with the accumulation of cytoplasmic TDP-43 ( Romano et al, 2020 ). TDP-43 cytoplasmic accumulation can be reduced via inhibition of ERK1/2, which triggers TDP-43 to re-enter the nucleus ( Romano et al, 2020 ).…”

Section: The Emergence Of Multi-system Proteinopathymentioning

confidence: 99%

“…In fibroblasts derived from patients with TARDBP mutations, abnormal metabolic activity and increases and indices of oxidative stress are associated with the accumulation of cytoplasmic TDP-43 ( Romano et al, 2020 ). TDP-43 cytoplasmic accumulation can be reduced via inhibition of ERK1/2, which triggers TDP-43 to re-enter the nucleus ( Romano et al, 2020 ). This implicates oxidative stress as a possible trigger to cause mis-localization of TDP-43, although it is unclear if alternative kinases can also phosphorylate TDP-43 instead of ERK1/2, or if ERK1/2 is in fact directly phosphorylating TDP-43.…”

Section: The Emergence Of Multi-system Proteinopathymentioning

confidence: 99%

“…Accumulation of misfolded proteins exacerbates oxidative stress and results in abnormal oxidative phosphorylation, while antioxidant treatment may help by reducing the stress induced by the misfolded proteins ( Debska-Vielhaber et al, 2021 ). Increased oxidative stress results in TDP-43 recruitment to stress granules ( Romano et al, 2020 ), which may then be pushed toward aggregation prone states.…”

Section: Mitochondrial Dysfunction As An Explanation For or A Downstream Consequence Of Rna Metabolism And Protein Homeostasis Failures?mentioning

confidence: 99%

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Proteinopathies as Hallmarks of Impaired Gene Expression, Proteostasis and Mitochondrial Function in Amyotrophic Lateral Sclerosis

et al. 2021

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Amyotrophic lateral sclerosis (ALS) is a fatal adult-onset neurodegenerative disease characterized by progressive degeneration of upper and lower motor neurons. As with the majority of neurodegenerative diseases, the pathological hallmarks of ALS involve proteinopathies which lead to the formation of various polyubiquitylated protein aggregates in neurons and glia. ALS is a highly heterogeneous disease, with both familial and sporadic forms arising from the convergence of multiple disease mechanisms, many of which remain elusive. There has been considerable research effort invested into exploring these disease mechanisms and in recent years dysregulation of RNA metabolism and mitochondrial function have emerged as of crucial importance to the onset and development of ALS proteinopathies. Widespread alterations of the RNA metabolism and post-translational processing of proteins lead to the disruption of multiple biological pathways. Abnormal mitochondrial structure, impaired ATP production, dysregulation of energy metabolism and calcium homeostasis as well as apoptosis have been implicated in the neurodegenerative process. Dysfunctional mitochondria further accumulate in ALS motor neurons and reflect a wider failure of cellular quality control systems, including mitophagy and other autophagic processes. Here, we review the evidence for RNA and mitochondrial dysfunction as some of the earliest critical pathophysiological events leading to the development of ALS proteinopathies, explore their relative pathological contributions and their points of convergence with other key disease mechanisms. This review will focus primarily on mutations in genes causing four major types of ALS (C9ORF72, SOD1, TARDBP/TDP-43, and FUS) and in protein homeostasis genes (SQSTM1, OPTN, VCP, and UBQLN2) as well as sporadic forms of the disease. Finally, we will look to the future of ALS research and how an improved understanding of central mechanisms underpinning proteinopathies might inform research directions and have implications for the development of novel therapeutic approaches.

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“…Nevertheless, alterations in the skin and other tissues may precede or appear concomitantly with neurological symptoms in some neurodegenerative diseases [ 13 ]. Despite the variability among the studies performed on either skin biopsies, cultured fibroblasts or engineered skin tissue, there is a common finding of TDP-43 cytoplasmic accumulation in the skin of sporadic and familial ALS patients [ 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 ]. Nonetheless, there is not a well-defined relationship with disease progression and other clinical features.…”

Section: Introductionmentioning

confidence: 99%

TDP-43 Cytoplasmic Translocation in the Skin Fibroblasts of ALS Patients

Rubio

Herrando-Grabulosa

Velasco

et al. 2022

Cells

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Diagnosis of ALS is based on clinical symptoms when motoneuron degeneration is significant. Therefore, new approaches for early diagnosis are needed. We aimed to assess if alterations in appearance and cellular localization of cutaneous TDP-43 may represent a biomarker for ALS. Skin biopsies from 64 subjects were analyzed: 44 ALS patients, 10 healthy controls (HC) and 10 neurological controls (NC) (Parkinson’s disease and multiple sclerosis). TDP-43 immunoreactivity in epidermis and dermis was analyzed, as well as the percentage of cells with TDP-43 cytoplasmic localization. We detected a higher amount of TDP-43 in epidermis (p < 0.001) and in both layers of dermis (p < 0.001), as well as a higher percentage of TDP-43 cytoplasmic positive cells (p < 0.001) in the ALS group compared to HC and NC groups. Dermal cells containing TDP-43 were fibroblasts as identified by co-labeling against vimentin. ROC analyses (AUC 0.867, p < 0.001; CI 95% 0.800–0.935) showed that detection of 24.1% cells with cytoplasmic TDP-43 positivity in the dermis had 85% sensitivity and 80% specificity for detecting ALS. We have identified significantly increased TDP-43 levels in epidermis and in the cytoplasm of dermal cells of ALS patients. Our findings provide support for the use of TDP-43 in skin biopsies as a potential biomarker.

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ALS skin fibroblasts reveal oxidative stress and ERK1/2-mediated cytoplasmic localization of TDP-43

Cited by 21 publications

References 60 publications

TDP-43 proteinopathies: a new wave of neurodegenerative diseases

TDP-43 proteinopathies: a new wave of neurodegenerative diseases

Proteinopathies as Hallmarks of Impaired Gene Expression, Proteostasis and Mitochondrial Function in Amyotrophic Lateral Sclerosis

TDP-43 Cytoplasmic Translocation in the Skin Fibroblasts of ALS Patients

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