Parkinson's disease (PD) is the most frequent neurodegenerative disorder after Alzheimer'... more Parkinson's disease (PD) is the most frequent neurodegenerative disorder after Alzheimer's disease, affecting about 4% of individuals over 80 years of age. Although it is known that advanced age represents one of the main risk factors for the development of PD, the relationship between the molecular alterations that accompany physiological ageing and the alterations that characterize this disease is still poorly understood. In recent years, cellular reprogramming has been used to produce models of several pathologies that affect cellular types that are not easily accessible otherwise. Induced pluripotent stem cells (IPSCs)-derived neurons represent a versatile model for the study of PD pathogenesis since they can be representative of neuronal deterioration, but appropriate experimental models are needed to recapitulate the age-related characteristics of the disease. Our work proposes to explore the relationship between cellular ageing and PD using dopaminergic neurons (DaNs)...
Alzheimer's disease (AD) is characterized by specific alterations of brain DNA methylation (D... more Alzheimer's disease (AD) is characterized by specific alterations of brain DNA methylation (DNAm) patterns. Age and sex, two major risk factors for AD, are also known to largely affect the epigenetic profiles in brain, but their contribution to AD-associated DNAm changes has been poorly investigated. In this study we considered publicly available DNAm datasets of four brain regions (temporal, frontal, entorhinal cortex, and cerebellum) from healthy adult subjects and AD patients, and performed a meta-analysis to identify sex-, age-, and AD-associated epigenetic profiles. In one of these datasets it was also possible to distinguish 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) profiles. We showed that DNAm differences between males and females tend to be shared between the four brain regions, while aging differently affects cortical regions compared to cerebellum. We found that the proportion of sex-dependent probes whose methylation is modified also during aging is h...
Urea cycle disorders are enzymopathies resulting from inherited deficiencies in any genes of the ... more Urea cycle disorders are enzymopathies resulting from inherited deficiencies in any genes of the cycle. In severe cases, currently available therapies are marginally effective, with liver transplantation being the only definitive treatment. Donor liver availability can limit even this therapy. Identification of novel therapeutics for genetic-based liver diseases requires models that provide measurable hepatic functions and phenotypes. Advances in stem cell and genome editing technologies could provide models for the investigation of cell-based genetic diseases, as well as the platforms for drug discovery. This report demonstrates a practical, and widely applicable, approach that includes the successful reprogramming of somatic cells from a patient with a urea cycle defect, their genetic correction and differentiation into hepatic organoids, and the subsequent demonstration of genetic and phenotypic change in the edited cells consistent with the correction of the defect. While indivi...
A growing amount of evidence suggests that the downregulation of protein synthesis is an adaptive... more A growing amount of evidence suggests that the downregulation of protein synthesis is an adaptive response during physiological aging, which positively contributes to longevity and can be modulated by nutritional interventions like caloric restriction (CR). The expression of ribosomal RNA (rRNA) is one of the main determinants of translational rate, and epigenetic modifications finely contribute to its regulation. Previous reports suggest that hypermethylation of ribosomal DNA (rDNA) locus occurs with aging, although with some species- and tissue- specificity. In the present study, we experimentally measured DNA methylation of three regions (the promoter, the 5′ of the 18S and the 5′ of 28S sequences) in the rDNA locus in liver tissues from rats at two, four, 10, and 18 months. We confirm previous findings, showing age-related hypermethylation, and describe, for the first time, that this gain in methylation also occurs in human hepatocytes. Furthermore, we show that age-related hype...
Parkinson's disease (PD) is the most frequent neurodegenerative disorder after Alzheimer'... more Parkinson's disease (PD) is the most frequent neurodegenerative disorder after Alzheimer's disease, affecting about 4% of individuals over 80 years of age. Although it is known that advanced age represents one of the main risk factors for the development of PD, the relationship between the molecular alterations that accompany physiological ageing and the alterations that characterize this disease is still poorly understood. In recent years, cellular reprogramming has been used to produce models of several pathologies that affect cellular types that are not easily accessible otherwise. Induced pluripotent stem cells (IPSCs)-derived neurons represent a versatile model for the study of PD pathogenesis since they can be representative of neuronal deterioration, but appropriate experimental models are needed to recapitulate the age-related characteristics of the disease. Our work proposes to explore the relationship between cellular ageing and PD using dopaminergic neurons (DaNs)...
Alzheimer's disease (AD) is characterized by specific alterations of brain DNA methylation (D... more Alzheimer's disease (AD) is characterized by specific alterations of brain DNA methylation (DNAm) patterns. Age and sex, two major risk factors for AD, are also known to largely affect the epigenetic profiles in brain, but their contribution to AD-associated DNAm changes has been poorly investigated. In this study we considered publicly available DNAm datasets of four brain regions (temporal, frontal, entorhinal cortex, and cerebellum) from healthy adult subjects and AD patients, and performed a meta-analysis to identify sex-, age-, and AD-associated epigenetic profiles. In one of these datasets it was also possible to distinguish 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) profiles. We showed that DNAm differences between males and females tend to be shared between the four brain regions, while aging differently affects cortical regions compared to cerebellum. We found that the proportion of sex-dependent probes whose methylation is modified also during aging is h...
Urea cycle disorders are enzymopathies resulting from inherited deficiencies in any genes of the ... more Urea cycle disorders are enzymopathies resulting from inherited deficiencies in any genes of the cycle. In severe cases, currently available therapies are marginally effective, with liver transplantation being the only definitive treatment. Donor liver availability can limit even this therapy. Identification of novel therapeutics for genetic-based liver diseases requires models that provide measurable hepatic functions and phenotypes. Advances in stem cell and genome editing technologies could provide models for the investigation of cell-based genetic diseases, as well as the platforms for drug discovery. This report demonstrates a practical, and widely applicable, approach that includes the successful reprogramming of somatic cells from a patient with a urea cycle defect, their genetic correction and differentiation into hepatic organoids, and the subsequent demonstration of genetic and phenotypic change in the edited cells consistent with the correction of the defect. While indivi...
A growing amount of evidence suggests that the downregulation of protein synthesis is an adaptive... more A growing amount of evidence suggests that the downregulation of protein synthesis is an adaptive response during physiological aging, which positively contributes to longevity and can be modulated by nutritional interventions like caloric restriction (CR). The expression of ribosomal RNA (rRNA) is one of the main determinants of translational rate, and epigenetic modifications finely contribute to its regulation. Previous reports suggest that hypermethylation of ribosomal DNA (rDNA) locus occurs with aging, although with some species- and tissue- specificity. In the present study, we experimentally measured DNA methylation of three regions (the promoter, the 5′ of the 18S and the 5′ of 28S sequences) in the rDNA locus in liver tissues from rats at two, four, 10, and 18 months. We confirm previous findings, showing age-related hypermethylation, and describe, for the first time, that this gain in methylation also occurs in human hepatocytes. Furthermore, we show that age-related hype...
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Papers by Francesco Ravaioli