Bioenergetic and proteolytic defects in fibroblasts from patients with sporadic Parkinson's disease

Giulia Ambrosi, Cristina Ghezzi, Sara Sepe, Chiara Milanese, Cesar Payan-Gomez, Cintia R. Bombardieri, Marie Therese Armentero, Roberta Zangaglia, Claudio Pacchetti, Pier Giorgio Mastroberardino, Fabio Blandini

Resultado de la investigación: Contribución a RevistaArtículo

32 Citas (Scopus)

Resumen

Background: Parkinson's disease (PD) is a complex disease and the current interest and focus of scientific research is both investigating the variety of causes that underlie PD pathogenesis, and identifying reliable biomarkers to diagnose and monitor the progression of pathology. Investigation on pathogenic mechanisms in peripheral cells, such as fibroblasts derived from patients with sporadic PD and age/gender matched controls, might generate deeper understanding of the deficits affecting dopaminergic neurons and, possibly, new tools applicable to clinical practice. Methods: Primary fibroblast cultures were established from skin biopsies. Increased susceptibility to the PD-related toxin rotenone was determined with apoptosis- and necrosis-specific cell death assays. Protein quality control was evaluated assessing the efficiency of the Ubiquitin Proteasome System (UPS) and protein levels of autophagic markers. Changes in cellular bioenergetics were monitored by measuring oxygen consumption and glycolysis-dependent medium acidification. The oxido-reductive status was determined by detecting mitochondrial superoxide production and oxidation levels in proteins and lipids. Results: PD fibroblasts showed higher vulnerability to necrotic cell death induced by complex I inhibitor rotenone, reduced UPS function and decreased maximal and rotenone-sensitive mitochondrial respiration. No changes in autophagy and redox markers were detected. Conclusions: Our study shows that increased susceptibility to rotenone and the presence of proteolytic and bioenergetic deficits that typically sustain the neurodegenerative process of PD can be detected in fibroblasts from idiopathic PD patients. Fibroblasts might therefore represent a powerful and minimally invasive tool to investigate PD pathogenic mechanisms, which might translate into considerable advances in clinical management of the disease. © 2014 Elsevier B.V.
Idioma originalEnglish (US)
Páginas (desde-hasta)1385-1394
Número de páginas10
PublicaciónBiochimica et Biophysica Acta - Molecular Basis of Disease
DOI
EstadoPublished - ene 1 2014

Huella dactilar

Energy Metabolism
Parkinson Disease
Fibroblasts
Rotenone
Proteasome Endopeptidase Complex
Ubiquitin
Cell Death
Proteins
Dopaminergic Neurons
Autophagy
Glycolysis
Disease Management
Oxygen Consumption
Superoxides
Quality Control
Oxidation-Reduction
Respiration
Necrosis
Biomarkers
Apoptosis

Citar esto

Ambrosi, Giulia ; Ghezzi, Cristina ; Sepe, Sara ; Milanese, Chiara ; Payan-Gomez, Cesar ; Bombardieri, Cintia R. ; Armentero, Marie Therese ; Zangaglia, Roberta ; Pacchetti, Claudio ; Mastroberardino, Pier Giorgio ; Blandini, Fabio. / Bioenergetic and proteolytic defects in fibroblasts from patients with sporadic Parkinson's disease. En: Biochimica et Biophysica Acta - Molecular Basis of Disease. 2014 ; pp. 1385-1394.
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title = "Bioenergetic and proteolytic defects in fibroblasts from patients with sporadic Parkinson's disease",
abstract = "Background: Parkinson's disease (PD) is a complex disease and the current interest and focus of scientific research is both investigating the variety of causes that underlie PD pathogenesis, and identifying reliable biomarkers to diagnose and monitor the progression of pathology. Investigation on pathogenic mechanisms in peripheral cells, such as fibroblasts derived from patients with sporadic PD and age/gender matched controls, might generate deeper understanding of the deficits affecting dopaminergic neurons and, possibly, new tools applicable to clinical practice. Methods: Primary fibroblast cultures were established from skin biopsies. Increased susceptibility to the PD-related toxin rotenone was determined with apoptosis- and necrosis-specific cell death assays. Protein quality control was evaluated assessing the efficiency of the Ubiquitin Proteasome System (UPS) and protein levels of autophagic markers. Changes in cellular bioenergetics were monitored by measuring oxygen consumption and glycolysis-dependent medium acidification. The oxido-reductive status was determined by detecting mitochondrial superoxide production and oxidation levels in proteins and lipids. Results: PD fibroblasts showed higher vulnerability to necrotic cell death induced by complex I inhibitor rotenone, reduced UPS function and decreased maximal and rotenone-sensitive mitochondrial respiration. No changes in autophagy and redox markers were detected. Conclusions: Our study shows that increased susceptibility to rotenone and the presence of proteolytic and bioenergetic deficits that typically sustain the neurodegenerative process of PD can be detected in fibroblasts from idiopathic PD patients. Fibroblasts might therefore represent a powerful and minimally invasive tool to investigate PD pathogenic mechanisms, which might translate into considerable advances in clinical management of the disease. {\circledC} 2014 Elsevier B.V.",
author = "Giulia Ambrosi and Cristina Ghezzi and Sara Sepe and Chiara Milanese and Cesar Payan-Gomez and Bombardieri, {Cintia R.} and Armentero, {Marie Therese} and Roberta Zangaglia and Claudio Pacchetti and Mastroberardino, {Pier Giorgio} and Fabio Blandini",
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month = "1",
day = "1",
doi = "10.1016/j.bbadis.2014.05.008",
language = "English (US)",
pages = "1385--1394",
journal = "Biochimica et Biophysica Acta - Molecular Basis of Disease",
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Ambrosi, G, Ghezzi, C, Sepe, S, Milanese, C, Payan-Gomez, C, Bombardieri, CR, Armentero, MT, Zangaglia, R, Pacchetti, C, Mastroberardino, PG & Blandini, F 2014, 'Bioenergetic and proteolytic defects in fibroblasts from patients with sporadic Parkinson's disease', Biochimica et Biophysica Acta - Molecular Basis of Disease, pp. 1385-1394. https://doi.org/10.1016/j.bbadis.2014.05.008

Bioenergetic and proteolytic defects in fibroblasts from patients with sporadic Parkinson's disease. / Ambrosi, Giulia; Ghezzi, Cristina; Sepe, Sara; Milanese, Chiara; Payan-Gomez, Cesar; Bombardieri, Cintia R.; Armentero, Marie Therese; Zangaglia, Roberta; Pacchetti, Claudio; Mastroberardino, Pier Giorgio; Blandini, Fabio.

En: Biochimica et Biophysica Acta - Molecular Basis of Disease, 01.01.2014, p. 1385-1394.

Resultado de la investigación: Contribución a RevistaArtículo

TY - JOUR

T1 - Bioenergetic and proteolytic defects in fibroblasts from patients with sporadic Parkinson's disease

AU - Ambrosi, Giulia

AU - Ghezzi, Cristina

AU - Sepe, Sara

AU - Milanese, Chiara

AU - Payan-Gomez, Cesar

AU - Bombardieri, Cintia R.

AU - Armentero, Marie Therese

AU - Zangaglia, Roberta

AU - Pacchetti, Claudio

AU - Mastroberardino, Pier Giorgio

AU - Blandini, Fabio

PY - 2014/1/1

Y1 - 2014/1/1

N2 - Background: Parkinson's disease (PD) is a complex disease and the current interest and focus of scientific research is both investigating the variety of causes that underlie PD pathogenesis, and identifying reliable biomarkers to diagnose and monitor the progression of pathology. Investigation on pathogenic mechanisms in peripheral cells, such as fibroblasts derived from patients with sporadic PD and age/gender matched controls, might generate deeper understanding of the deficits affecting dopaminergic neurons and, possibly, new tools applicable to clinical practice. Methods: Primary fibroblast cultures were established from skin biopsies. Increased susceptibility to the PD-related toxin rotenone was determined with apoptosis- and necrosis-specific cell death assays. Protein quality control was evaluated assessing the efficiency of the Ubiquitin Proteasome System (UPS) and protein levels of autophagic markers. Changes in cellular bioenergetics were monitored by measuring oxygen consumption and glycolysis-dependent medium acidification. The oxido-reductive status was determined by detecting mitochondrial superoxide production and oxidation levels in proteins and lipids. Results: PD fibroblasts showed higher vulnerability to necrotic cell death induced by complex I inhibitor rotenone, reduced UPS function and decreased maximal and rotenone-sensitive mitochondrial respiration. No changes in autophagy and redox markers were detected. Conclusions: Our study shows that increased susceptibility to rotenone and the presence of proteolytic and bioenergetic deficits that typically sustain the neurodegenerative process of PD can be detected in fibroblasts from idiopathic PD patients. Fibroblasts might therefore represent a powerful and minimally invasive tool to investigate PD pathogenic mechanisms, which might translate into considerable advances in clinical management of the disease. © 2014 Elsevier B.V.

AB - Background: Parkinson's disease (PD) is a complex disease and the current interest and focus of scientific research is both investigating the variety of causes that underlie PD pathogenesis, and identifying reliable biomarkers to diagnose and monitor the progression of pathology. Investigation on pathogenic mechanisms in peripheral cells, such as fibroblasts derived from patients with sporadic PD and age/gender matched controls, might generate deeper understanding of the deficits affecting dopaminergic neurons and, possibly, new tools applicable to clinical practice. Methods: Primary fibroblast cultures were established from skin biopsies. Increased susceptibility to the PD-related toxin rotenone was determined with apoptosis- and necrosis-specific cell death assays. Protein quality control was evaluated assessing the efficiency of the Ubiquitin Proteasome System (UPS) and protein levels of autophagic markers. Changes in cellular bioenergetics were monitored by measuring oxygen consumption and glycolysis-dependent medium acidification. The oxido-reductive status was determined by detecting mitochondrial superoxide production and oxidation levels in proteins and lipids. Results: PD fibroblasts showed higher vulnerability to necrotic cell death induced by complex I inhibitor rotenone, reduced UPS function and decreased maximal and rotenone-sensitive mitochondrial respiration. No changes in autophagy and redox markers were detected. Conclusions: Our study shows that increased susceptibility to rotenone and the presence of proteolytic and bioenergetic deficits that typically sustain the neurodegenerative process of PD can be detected in fibroblasts from idiopathic PD patients. Fibroblasts might therefore represent a powerful and minimally invasive tool to investigate PD pathogenic mechanisms, which might translate into considerable advances in clinical management of the disease. © 2014 Elsevier B.V.

U2 - 10.1016/j.bbadis.2014.05.008

DO - 10.1016/j.bbadis.2014.05.008

M3 - Article

SP - 1385

EP - 1394

JO - Biochimica et Biophysica Acta - Molecular Basis of Disease

JF - Biochimica et Biophysica Acta - Molecular Basis of Disease

SN - 0925-4439

ER -