Andrea Ghiroldi | University of Pavia (original) (raw)

Papers by Andrea Ghiroldi

Research paper thumbnail of Adenine phosphoribosyltransferase (APRT) deficiency: identification of a novel nonsense mutation

BMC nephrology, 2014

Adenine phosphoribosyltransferase deficiency (APRTD) is an under estimated genetic form of kidney... more Adenine phosphoribosyltransferase deficiency (APRTD) is an under estimated genetic form of kidney stones and/or kidney failure, characterized by intratubular precipitation of 2,8-dihydroxyadenine crystals (2,8-DHA). Currently, five pathologic allelic variants have been identified as responsible of the complete inactivation of APRT protein. In this study, we report a novel nonsense mutation of the APRT gene from a 47- year old Italian patient. The mutation, localized in the exon 5, leads to the replacement of a cytosine with a thymine (g.2098C > T), introducing a stop codon at amino acid position 147 (p.Gln147X).This early termination was deleterious for the enzyme structural and functional integrity, as demonstrated by the structure analysis and the activity assay of the mutant APRT protein. These data revealed that the p.Gln147X mutation in APRT gene might be a new cause of APRT disease.

Research paper thumbnail of Altered Intracellular Localization of SOD1 in Leukocytes from Patients with Sporadic Amyotrophic Lateral Sclerosis

PLoS ONE, 2013

Several lines of evidence support the hypothesis of a toxic role played by wild type SOD1 (WT-SOD... more Several lines of evidence support the hypothesis of a toxic role played by wild type SOD1 (WT-SOD1) in the pathogenesis of sporadic amyotrophic lateral sclerosis (SALS). In this study we investigated both distribution and expression profile of WT-SOD1 in leukocytes from 19 SALS patients and 17 healthy individuals. Immunofluorescence experiments by confocal microscopy showed that SOD1 accumulates in the nuclear compartment in a group of SALS subjects. These results were also confirmed by western blot carried out on soluble nuclear and cytoplasmic fractions, with increased nuclear SOD1 level (p,0.05). In addition, we observed the presence of cytoplasmic SOD1 aggregates in agreement with an increased amount of the protein recovered by the insoluble fraction. A further confirmation of the overall increased level of SOD1 has been obtained from single cells analysis using flow cytometry as cells from SALS patients showed an higher SOD1 protein content (p,0.05). These findings add further evidence to the hypothesis of an altered WT-SOD1 expression profile in peripheral blood mononuclear cells (PBMCs) from patients with ALS suggesting that WT-SOD1 species with different degrees of solubility could be involved in the pathogenesis of the disease.

Research paper thumbnail of A new GLUT-1 mutation in a family with glucose transporter 1 deficiency syndrome

Research paper thumbnail of 441 Possible Disease Markers in BAL Fluid of BOS Patients

The Journal of Heart and Lung Transplantation, 2011

Purpose: Cardiopulmonary exercise testing (CPET) is a known predictor of all cause mortality in h... more Purpose: Cardiopulmonary exercise testing (CPET) is a known predictor of all cause mortality in heart failure, emphysema and normal populations but has not been used post lung transplant (LnTx). We hypothesize that CPET at 1 year post LnTx is a predictor of all cause mortality, conditioned on one-year survival.

Research paper thumbnail of G93A SOD1 alters cell cycle in a cellular model of Amyotrophic Lateral Sclerosis

Cellular Signalling, 2010

Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative multifactorial disease characterized, ... more Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative multifactorial disease characterized, like other diseases such as Alzheimer's disease (AD), Parkinson's disease (PD) or frontotemporal dementia (FTD), by the degeneration of specific neuronal cell populations. Motor neuron loss is distinctive of ALS. However, the causes of onset and progression of motor neuron death are still largely unknown. In about 2% of all cases, mutations in the gene encoding for the Cu/Zn superoxide dismutase (SOD1) are implicated in the disease. Several alterations in the expression or activation of cell cycle proteins have been described in the neurodegenerative diseases and related to cell death. In this work we show that mutant SOD1 can alter cell cycle in a cellular model of ALS. Our findings suggest that modifications in the cell cycle progression could be due to an increased interaction between mutant G93A SOD1 and Bcl-2 through the cyclins regulator p27. As previously described in post mitotic neurons, cell cycle alterations could fatally lead to cell death.

Research paper thumbnail of Adenine phosphoribosyltransferase (APRT) deficiency: identification of a novel nonsense mutation

BMC nephrology, 2014

Adenine phosphoribosyltransferase deficiency (APRTD) is an under estimated genetic form of kidney... more Adenine phosphoribosyltransferase deficiency (APRTD) is an under estimated genetic form of kidney stones and/or kidney failure, characterized by intratubular precipitation of 2,8-dihydroxyadenine crystals (2,8-DHA). Currently, five pathologic allelic variants have been identified as responsible of the complete inactivation of APRT protein. In this study, we report a novel nonsense mutation of the APRT gene from a 47- year old Italian patient. The mutation, localized in the exon 5, leads to the replacement of a cytosine with a thymine (g.2098C > T), introducing a stop codon at amino acid position 147 (p.Gln147X).This early termination was deleterious for the enzyme structural and functional integrity, as demonstrated by the structure analysis and the activity assay of the mutant APRT protein. These data revealed that the p.Gln147X mutation in APRT gene might be a new cause of APRT disease.

Research paper thumbnail of Altered Intracellular Localization of SOD1 in Leukocytes from Patients with Sporadic Amyotrophic Lateral Sclerosis

PLoS ONE, 2013

Several lines of evidence support the hypothesis of a toxic role played by wild type SOD1 (WT-SOD... more Several lines of evidence support the hypothesis of a toxic role played by wild type SOD1 (WT-SOD1) in the pathogenesis of sporadic amyotrophic lateral sclerosis (SALS). In this study we investigated both distribution and expression profile of WT-SOD1 in leukocytes from 19 SALS patients and 17 healthy individuals. Immunofluorescence experiments by confocal microscopy showed that SOD1 accumulates in the nuclear compartment in a group of SALS subjects. These results were also confirmed by western blot carried out on soluble nuclear and cytoplasmic fractions, with increased nuclear SOD1 level (p,0.05). In addition, we observed the presence of cytoplasmic SOD1 aggregates in agreement with an increased amount of the protein recovered by the insoluble fraction. A further confirmation of the overall increased level of SOD1 has been obtained from single cells analysis using flow cytometry as cells from SALS patients showed an higher SOD1 protein content (p,0.05). These findings add further evidence to the hypothesis of an altered WT-SOD1 expression profile in peripheral blood mononuclear cells (PBMCs) from patients with ALS suggesting that WT-SOD1 species with different degrees of solubility could be involved in the pathogenesis of the disease.

Research paper thumbnail of A new GLUT-1 mutation in a family with glucose transporter 1 deficiency syndrome

Research paper thumbnail of 441 Possible Disease Markers in BAL Fluid of BOS Patients

The Journal of Heart and Lung Transplantation, 2011

Purpose: Cardiopulmonary exercise testing (CPET) is a known predictor of all cause mortality in h... more Purpose: Cardiopulmonary exercise testing (CPET) is a known predictor of all cause mortality in heart failure, emphysema and normal populations but has not been used post lung transplant (LnTx). We hypothesize that CPET at 1 year post LnTx is a predictor of all cause mortality, conditioned on one-year survival.

Research paper thumbnail of G93A SOD1 alters cell cycle in a cellular model of Amyotrophic Lateral Sclerosis

Cellular Signalling, 2010

Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative multifactorial disease characterized, ... more Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative multifactorial disease characterized, like other diseases such as Alzheimer's disease (AD), Parkinson's disease (PD) or frontotemporal dementia (FTD), by the degeneration of specific neuronal cell populations. Motor neuron loss is distinctive of ALS. However, the causes of onset and progression of motor neuron death are still largely unknown. In about 2% of all cases, mutations in the gene encoding for the Cu/Zn superoxide dismutase (SOD1) are implicated in the disease. Several alterations in the expression or activation of cell cycle proteins have been described in the neurodegenerative diseases and related to cell death. In this work we show that mutant SOD1 can alter cell cycle in a cellular model of ALS. Our findings suggest that modifications in the cell cycle progression could be due to an increased interaction between mutant G93A SOD1 and Bcl-2 through the cyclins regulator p27. As previously described in post mitotic neurons, cell cycle alterations could fatally lead to cell death.