Functional analysis of POLD1 p.ser605del variant: the aging phenotype of MDPL syndrome is associated with an impaired DNA repair capacity

Murdocca, Michela; Spitalieri, Paola; Masi, Claudia De; Udroiu, Ion; Marinaccio, Jessica; Sanchez, Massimo; Talarico, Rosa Valentina; D’Adamo, Monica; Sbraccia, Paolo; D’Apice, Maria Rosaria; Novelli, Giuseppe; Sgura, Antonella; Sangiuolo, Federica

doi:10.18632/aging.202680

Cited by 13 publications

(22 citation statements)

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“…In previous in vitro studies [1,2] we demonstrated several hallmarks of senescence and of LMNA-linked progeria in MDPL fibroblasts. In particular, MDPL cells exhibited micronuclei, nuclear architecture abnormalities, and prelamin A aggregation.…”

Section: Introductionmentioning

confidence: 68%

“…In a previous paper [2], we elucidated some aspects related to p.Ser605del mutation in MDPL fibroblasts and identified nuclear and cellular alterations also encountered in other Progeroid Syndromes. These include an impairment of nuclear envelope, accumulation of prelamin A, altered cell growth, cellular senescence, compromised ability to repair DNA double-strand breaks, presence of micronuclei and an increase rate of telomere shortening.…”

Section: Discussionmentioning

confidence: 99%

“…We previously described different alterations of nuclear shape in MDPL HDFs, together with a high frequency of micronuclei [1,2]. In order to analyze the therapeutic potential of metformin for the MDPL disease, HDFs were treated with metformin administration to explore any effects on both impairment of nuclear shape and presence of micronuclei.…”

Section: Metformin Treatment: Nuclear Envelope Characterization and M...mentioning

confidence: 99%

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Mitochondrial dysfunction in mandibular hypoplasia, deafness and progeroid features with concomitant lipodystrophy (MDPL) patients

Murdocca

Spitalieri

Cappello

et al. 2022

Aging

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Mandibular hypoplasia, Deafness and Progeroid features with concomitant Lipodystrophy is a rare, genetic, premature aging disease named MDPL Syndrome, due to almost always a de novo variant in POLD1 gene, encoding the DNA polymerase δ. In previous in vitro studies, we have already described several hallmarks of aging, including genetic damage, telomere shortening, cell senescence and proliferation defects. Since a clear connection has been reported between telomere shortening and mitochondria malfunction to initiate the aging process, we explored the role that mitochondrial metabolism and activity play in pathogenesis of MDPL Syndrome, an aspect that has not been addressed yet. We thus evaluated mtDNA copy number, assessing a significant decrease in mutated cells. The expression level of genes related to mitochondrial biogenesis and activity also revealed a significant reduction, highlighting a mitochondrial dysfunction in MDPL cells. Even the expression levels of mitochondrial marker SOD2, as assessed by immunofluorescence, were reduced. The decrease in this antioxidant enzyme correlated with increased production of mitochondrial ROS in MDPL cells, compared to WT. Consistent with these data, Focused Ion Beam/Scanning Electron Microscopy (FIB/SEM) analysis revealed in MDPL cells fewer mitochondria, which also displayed morphological abnormalities. Accordingly, we detected autophagic vacuoles containing partially digested mitochondria. Overall, our results demonstrate a dramatic impairment of mitochondrial biogenesis and activity in MDPL Syndrome. Administration of Metformin, though unable to restore mitochondrial impairment, proved efficient in rescuing nuclear abnormalities, suggesting its use to specifically ameliorate the premature aging phenotype.www.aging-us.com AGINGG0/G1 phase. Furthermore, telomere shortening was faster in MDPL cells, proposing their malfunction as a relevant trait in MDPL syndrome.Current papers have reported that telomere shortening may also influence mitochondria activity through many pathways to begin the aging process, among which the nuclear-mitochondrial signalling [3]. Adaptive response to such damage involves peroxisome proliferatoractivated receptor gamma co-activator 1a (PGC-1a), a master regulator of mitochondrial biogenesis and activity, which is activated by SIRT1. In turn, PGC-1a induces the expression of mitochondrial antioxidant enzyme superoxide dismutase 2 (SOD2).

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Section: Introductionmentioning

confidence: 68%

Section: Discussionmentioning

confidence: 99%

Section: Metformin Treatment: Nuclear Envelope Characterization and M...mentioning

confidence: 99%

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Mitochondrial dysfunction in mandibular hypoplasia, deafness and progeroid features with concomitant lipodystrophy (MDPL) patients

Murdocca

Spitalieri

Cappello

et al. 2022

Aging

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“…[42][43][44][45][46][47][48][49][50][51] Interestingly, MDPL fibroblasts carrying the recurrent POLD1 p.Ser605del mutation showed nuclear and cellular alterations resembling features observed in other progeroid syndromes, including severe nuclear envelope anomalies, accumulation of prelamin A, altered cell growth, cellular senescence, impaired ability to repair DNA double-strand breaks (DSBs), presence of micronuclei, and an increased rate of telomere shortening, suggesting that the ageing phenotype of MDPL syndrome is associated with an impaired DNA repair capacity. 52…”

Section: Mandibuloacral Dysplasia Resulting From Mutations Of Pold1 and Mtx2 Genesmentioning

confidence: 99%

Mutations Involved in Premature-Ageing Syndromes

Coppedè¹

2021

TACG

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Premature-ageing syndromes are a heterogeneous group of rare genetic disorders resembling features of accelerated ageing and resulting from mutations in genes coding for proteins required for nuclear lamina architecture, DNA repair and maintenance of genome stability, mitochondrial function and other cellular processes. Hutchinson–Gilford progeria syndrome (HGPS) and Werner syndrome (WS) are two of the best-characterized progeroid syndromes referred to as childhood- and adulthood-progeria, respectively. This article provides an updated overview of the mutations leading to HGPS, WS, and to the spectrum of premature-ageing laminopathies ranging in severity from congenital restrictive dermopathy (RD) to adult-onset atypical WS, including RD-like laminopathies, typical and atypical HGPS, more and less severe forms of mandibuloacral dysplasia (MAD), Néstor-Guillermo progeria syndrome (NGPS), atypical WS, and atypical progeroid syndromes resembling features of HGPS and/or MAD but resulting from impaired DNA repair or mitochondrial functions, including mandibular hypoplasia, deafness, progeroid features, and lipodystrophy (MDPL) syndrome and mandibuloacral dysplasia associated to MTX2 (MADaM). The overlapping signs and symptoms among different premature-ageing syndromes, resulting from both a large genetic heterogeneity and shared pathological pathways underlying these conditions, require an expert clinical evaluation in specialized centers paralleled by next-generation sequencing of panels of genes involved in these disorders in order to establish as early as possible an accurate clinical and molecular diagnosis for a proper patient management.

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“…Lipodystrophy is associated with a predisposition to cancer in Werner syndrome, as well as in Bloom syndrome, due to mutations in BLM encoding a DNA helicase, or in ataxia-telangiectasia with altered DNA synthesis and excision-repair pathways ( 106 ). Cultured fibroblasts from patients with Werner or MDPL syndromes present signs of premature senescence ( 81 , 107 ). Importantly, premature senescence was shown to impair adipogenesis in human pluripotent stem cells lacking either WRN or BLM helicases ( 108 ).…”

Section: Lipodystrophy and Ageingmentioning

confidence: 99%

Molecular and Cellular Bases of Lipodystrophy Syndromes

et al. 2022

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Lipodystrophy syndromes are rare diseases originating from a generalized or partial loss of adipose tissue. Adipose tissue dysfunction results from heterogeneous genetic or acquired causes, but leads to similar metabolic complications with insulin resistance, diabetes, hypertriglyceridemia, nonalcoholic fatty liver disease, dysfunctions of the gonadotropic axis and endocrine defects of adipose tissue with leptin and adiponectin deficiency. Diagnosis, based on clinical and metabolic investigations, and on genetic analyses, is of major importance to adapt medical care and genetic counseling. Molecular and cellular bases of these syndromes involve, among others, altered adipocyte differentiation, structure and/or regulation of the adipocyte lipid droplet, and/or premature cellular senescence. Lipodystrophy syndromes frequently present as systemic diseases with multi-tissue involvement. After an update on the main molecular bases and clinical forms of lipodystrophy, we will focus on topics that have recently emerged in the field. We will discuss the links between lipodystrophy and premature ageing and/or immuno-inflammatory aggressions of adipose tissue, as well as the relationships between lipomatosis and lipodystrophy. Finally, the indications of substitutive therapy with metreleptin, an analog of leptin, which is approved in Europe and USA, will be discussed.

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Functional analysis of POLD1 p.ser605del variant: the aging phenotype of MDPL syndrome is associated with an impaired DNA repair capacity

Cited by 13 publications

References 30 publications

Mitochondrial dysfunction in mandibular hypoplasia, deafness and progeroid features with concomitant lipodystrophy (MDPL) patients

Mitochondrial dysfunction in mandibular hypoplasia, deafness and progeroid features with concomitant lipodystrophy (MDPL) patients

Mutations Involved in Premature-Ageing Syndromes

Molecular and Cellular Bases of Lipodystrophy Syndromes

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