Toward an Early Diagnosis for Alzheimer’s Disease Based on the Perinuclear Localization of the ATM Protein

Berthel, Elise; Praly, Laurent; Reun, Eymeric Le; Sonzogni, Laurène; Al-Choboq, Joëlle; Chekroun, Abdennasser; Granzotto, Adeline; Devic, Clément; Ferlazzo, Mélanie L.; Pereira, Sandrine; Bourguignon, M.; Foray, Nicolas

doi:10.3390/cells12131747

Cited by 7 publications

(14 citation statements)

References 49 publications

(129 reference statements)

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“…Recently, in this journal, we have pointed out that fibroblasts from patients suffering from Alzheimer’s disease (AD) specifically show spontaneous perinuclear pATM crowns [ 34 ]. The perinuclear pATM crowns were found to be the result of the progressive accumulation of ATM monomers in response to permanent endogenous and exogenous oxidative stress.…”

Section: Resultsmentioning

confidence: 99%

“…Furthermore, more recently, the X-proteins associated with aging syndromes have been found either attached to the nuclear membranes or in close proximity to them. Consequently, in cells from aging syndromes, ATM monomers bound to the X-proteins may specifically form perinuclear pATM crowns, easily quantifiable by immunofluorescence [ 33 , 34 ]. Altogether, the RIANS model biomarkers may discriminate between cancer proneness and aging [ 33 , 34 ].…”

Section: Introductionmentioning

confidence: 99%

“…Consequently, in cells from aging syndromes, ATM monomers bound to the X-proteins may specifically form perinuclear pATM crowns, easily quantifiable by immunofluorescence [ 33 , 34 ]. Altogether, the RIANS model biomarkers may discriminate between cancer proneness and aging [ 33 , 34 ]. To verify and document such hypotheses, the goal of this study was to perform the radiobiological characterization of human and porcine epithelial lens cells by using RIANS biomarkers and to identify some X-proteins that would be specific to lens aging and the process of RI cataractogenesis.…”

Section: Introductionmentioning

confidence: 99%

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The Radiobiological Characterization of Human and Porcine Lens Cells Suggests the Importance of the ATM Kinase in Radiation-Induced Cataractogenesis

Al-Choboq,

Mathis,

Restier-Verlet

et al. 2023

Cells

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Studies about radiation-induced human cataractogenesis are generally limited by (1) the poor number of epithelial lens cell lines available (likely because of the difficulties of cell sampling and amplification) and (2) the lack of reliable biomarkers of the radiation-induced aging process. We have developed a mechanistic model of the individual response to radiation based on the nucleoshuttling of the ATM protein (RIANS). Recently, in the frame of the RIANS model, we have shown that, to respond to permanent endo- and exogenous stress, the ATM protein progressively agglutinates around the nucleus attracted by overexpressed perinuclear ATM-substrate protein. As a result, perinuclear ATM crowns appear to be an interesting biomarker of aging. The radiobiological characterization of the two human epithelial lens cell lines available and the four porcine epithelial lens cell lines that we have established showed delayed RIANS. The BFSP2 protein, found specifically overexpressed around the lens cell nucleus and interacting with ATM, may be a specific ATM-substrate protein facilitating the formation of perinuclear ATM crowns in lens cells. The perinuclear ATM crowns were observed inasmuch as the number of culture passages is high. Interestingly, 2 Gy X-rays lead to the transient disappearance of the perinuclear ATM crowns. Altogether, our findings suggest a strong influence of the ATM protein in radiation-induced cataractogenesis.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The Radiobiological Characterization of Human and Porcine Lens Cells Suggests the Importance of the ATM Kinase in Radiation-Induced Cataractogenesis

Al-Choboq,

Mathis,

Restier-Verlet

et al. 2023

Cells

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“…Activation of mtUPR has been proposed as a therapeutic target in several diseases [15,78,79], encompassing neurodegenerative [80][81][82][83][84][85][86], cardiovascular [87][88][89][90][91], metabolic [92][93][94], cancer [95][96][97][98][99][100][101][102][103][104][105][106], and mitochondrial diseases [8,14]. Taking advantage of this and the screening system based on cell culture in galactose medium, we tested different activators of mtUPR.…”

Section: Discussionmentioning

confidence: 99%

Polydatin and Nicotinamide Rescue the Cellular Phenotype of Mitochondrial Diseases by Mitochondrial Unfolded Protein Response (mtUPR) Activation

Cilleros-Holgado,

Gómez-Fernández,

Piñero-Pérez

et al. 2024

Biomolecules

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Primary mitochondrial diseases result from mutations in nuclear DNA (nDNA) or mitochondrial DNA (mtDNA) genes, encoding proteins crucial for mitochondrial structure or function. Given that few disease-specific therapies are available for mitochondrial diseases, novel treatments to reverse mitochondrial dysfunction are necessary. In this work, we explored new therapeutic options in mitochondrial diseases using fibroblasts and induced neurons derived from patients with mutations in the GFM1 gene. This gene encodes the essential mitochondrial translation elongation factor G1 involved in mitochondrial protein synthesis. Due to the severe mitochondrial defect, mutant GFM1 fibroblasts cannot survive in galactose medium, making them an ideal screening model to test the effectiveness of pharmacological compounds. We found that the combination of polydatin and nicotinamide enabled the survival of mutant GFM1 fibroblasts in stress medium. We also demonstrated that polydatin and nicotinamide upregulated the mitochondrial Unfolded Protein Response (mtUPR), especially the SIRT3 pathway. Activation of mtUPR partially restored mitochondrial protein synthesis and expression, as well as improved cellular bioenergetics. Furthermore, we confirmed the positive effect of the treatment in GFM1 mutant induced neurons obtained by direct reprogramming from patient fibroblasts. Overall, we provide compelling evidence that mtUPR activation is a promising therapeutic strategy for GFM1 mutations.

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“…This prevents or delays the ATM shuttling from the cytoplasm to the nucleus and blocks the repair of damaged DNA. This knowledge shows, perhaps for the first time, that ATM-kinase is involved in the pathophysiology of AD and that the presence of this crown may support early diagnosis and treatment monitoring in AD [ 6 ].…”

Section: Introductionmentioning

confidence: 99%

Friends and Foes in Alzheimer’s Disease

Pauwels,

Boer

2023

Med Princ Pract

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Alzheimer’s disease (AD) is a disabling neurodegenerative disease. The prognosis is poor and currently there are no proven effective therapies. Most likely, the etiology is related to cerebral inflammatory processes that cause neuronal damage, resulting in dysfunction and apoptosis of nerve cells. Pathogens that evoke a neuroinflammatory response, collectively activate astrocytes and microglia, which contributes to the secretion of pro-inflammatory cytokines. This leads to the deposit of clustered fragments of beta-amyloid and misfolded tau proteins which do not elicit an adequate immune reaction. Apart from the function of astrocytes and microglia, molecular entities such as TREM2, SYK, C22 and C33 play a role in the physiopathology of AD. Furthermore, bacteria and viruses may trigger an overactive inflammatory response in the brain. Pathogens like Heliobacter pylori, Chlamydia pneumonia and Porphyromonas gingivalis (known for low-grade infection in the oral cavity) can release gingipains, which are enzymes that can damage and destroy neurons. Chronic infection with Borrelia burgdorferi (the causative agent of Lyme disease) can co-localize with tau-tangles and amyloid deposits. As for viral infections, HSV1, cytomegalovirus and Epstein-Barr virus can play a role in the pathogenesis of AD. Present investigations have resulted in the development of antibodies that can clear the brain of beta-amyloid plaques. Trials with humanized aducanumab, lecanomab and donanemab revealed limited success in AD patients. However, AD should be considered as a continuum in which the initial preclinical phase may take 10 or even 20 years. It is generally thought that this phase offers a window for efficacious treatment. Therefore, research is also focused on the identification of biomarkers for early AD detection. In this respect, the plasma measurement of neurofilament light chain in patients treated with hydromethylthionine mesylate may well open a new way to prevent the formation of tau tangles and represents the first treatment for AD at its roots.

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Toward an Early Diagnosis for Alzheimer’s Disease Based on the Perinuclear Localization of the ATM Protein

Cited by 7 publications

References 49 publications

The Radiobiological Characterization of Human and Porcine Lens Cells Suggests the Importance of the ATM Kinase in Radiation-Induced Cataractogenesis

The Radiobiological Characterization of Human and Porcine Lens Cells Suggests the Importance of the ATM Kinase in Radiation-Induced Cataractogenesis

Polydatin and Nicotinamide Rescue the Cellular Phenotype of Mitochondrial Diseases by Mitochondrial Unfolded Protein Response (mtUPR) Activation

Friends and Foes in Alzheimer’s Disease

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