Bioenergetics and Autophagic imbalance in Patients-Derived Cell Models of Parkinson Disease Supports Systemic Dysfunction in Neurodegeneration

Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder worldwide affecting 2-3% of the population over 65 years. This prevalence is expected to rise as life expectancy increases and diagnostic and therapeutic protocols improve. PD encompasses a multitude of clinical, g...

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Authors: González Casacuberta, Ingrid, Juárez Flores, Diana Luz, Morén Núñez, Constanza, Garrabou Tornos, Glòria
Format: article
Status:Published version
Publication Date:2019
Country:España
Institution:Universidad de Barcelona
Repository:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/175776
Online Access:https://hdl.handle.net/2445/175776
Access Level:Open access
Keyword:Malalties neurodegeneratives
Autofàgia
Malaltia de Parkinson
Neurodegenerative Diseases
Autophagy
Parkinson's disease
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spelling Bioenergetics and Autophagic imbalance in Patients-Derived Cell Models of Parkinson Disease Supports Systemic Dysfunction in NeurodegenerationGonzález Casacuberta, IngridJuárez Flores, Diana LuzMorén Núñez, ConstanzaGarrabou Tornos, GlòriaMalalties neurodegenerativesAutofàgiaMalaltia de ParkinsonNeurodegenerative DiseasesAutophagyParkinson's diseaseParkinson's disease (PD) is the second most prevalent neurodegenerative disorder worldwide affecting 2-3% of the population over 65 years. This prevalence is expected to rise as life expectancy increases and diagnostic and therapeutic protocols improve. PD encompasses a multitude of clinical, genetic, and molecular forms of the disease. Even though the mechanistic of the events leading to neurodegeneration remain largely unknown, some molecular hallmarks have been repeatedly reported in most patients and models of the disease. Neuroinflammation, protein misfolding, disrupted endoplasmic reticulum-mitochondria crosstalk, mitochondrial dysfunction and consequent bioenergetic failure, oxidative stress and autophagy deregulation, are amongst the most commonly described. Supporting these findings, numerous familial forms of PD are caused by mutations in genes that are crucial for mitochondrial and autophagy proper functioning. For instance, late and early onset PD associated to mutations in Leucine-rich repeat kinase 2 (LRRK2) and Parkin (PRKN) genes, responsible for the most frequent dominant and recessive inherited forms of PD, respectively, have emerged as promising examples of disease due to their established role in commanding bioenergetic and autophagic balance. Concomitantly, the development of animal and cell models to investigate the etiology of the disease, potential biomarkers and therapeutic approaches are being explored. One of the emerging approaches in this context is the use of patient's derived cells models, such as skin-derived fibroblasts that preserve the genetic background and some environmental cues of the patients. An increasing number of reports in these PD cell models postulate that deficient mitochondrial function and impaired autophagic flux may be determinant in PD accelerated nigral cell death in terms of limitation of cell energy supply and accumulation of obsolete and/or unfolded proteins or dysfunctional organelles. The reliance of neurons on mitochondrial oxidative metabolism and their post-mitotic nature, may explain their increased vulnerability to undergo degeneration upon mitochondrial challenges or autophagic insults. In this scenario, proper mitochondrial function and turnover through mitophagy, are gaining in strength as protective targets to prevent neurodegeneration, together with the use of patient-derived fibroblasts to further explore these events. These findings point out the presence of molecular damage beyond the central nervous system (CNS) and proffer patient-derived cell platforms to the clinical and scientific community, which enable the study of disease etiopathogenesis and therapeutic approaches focused on modifying the natural history of PD through, among others, the enhancement of mitochondrial function and autophagy.Frontiers Media2019info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://hdl.handle.net/2445/175776Articles publicats en revistes (Medicina)reponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaInglésReproducció del document publicat a: https://doi.org/10.3389/fnins.2019.00894Frontiers in Neuroscience, 2019, vol. 13https://doi.org/10.3389/fnins.2019.00894cc-by (c) González Casacuberta, Ingrid et al., 2019http://creativecommons.org/licenses/by/3.0/esinfo:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/1757762026-05-27T06:46:51Z
dc.title.none.fl_str_mv Bioenergetics and Autophagic imbalance in Patients-Derived Cell Models of Parkinson Disease Supports Systemic Dysfunction in Neurodegeneration
title Bioenergetics and Autophagic imbalance in Patients-Derived Cell Models of Parkinson Disease Supports Systemic Dysfunction in Neurodegeneration
spellingShingle Bioenergetics and Autophagic imbalance in Patients-Derived Cell Models of Parkinson Disease Supports Systemic Dysfunction in Neurodegeneration
González Casacuberta, Ingrid
Malalties neurodegeneratives
Autofàgia
Malaltia de Parkinson
Neurodegenerative Diseases
Autophagy
Parkinson's disease
title_short Bioenergetics and Autophagic imbalance in Patients-Derived Cell Models of Parkinson Disease Supports Systemic Dysfunction in Neurodegeneration
title_full Bioenergetics and Autophagic imbalance in Patients-Derived Cell Models of Parkinson Disease Supports Systemic Dysfunction in Neurodegeneration
title_fullStr Bioenergetics and Autophagic imbalance in Patients-Derived Cell Models of Parkinson Disease Supports Systemic Dysfunction in Neurodegeneration
title_full_unstemmed Bioenergetics and Autophagic imbalance in Patients-Derived Cell Models of Parkinson Disease Supports Systemic Dysfunction in Neurodegeneration
title_sort Bioenergetics and Autophagic imbalance in Patients-Derived Cell Models of Parkinson Disease Supports Systemic Dysfunction in Neurodegeneration
dc.creator.none.fl_str_mv González Casacuberta, Ingrid
Juárez Flores, Diana Luz
Morén Núñez, Constanza
Garrabou Tornos, Glòria
author González Casacuberta, Ingrid
author_facet González Casacuberta, Ingrid
Juárez Flores, Diana Luz
Morén Núñez, Constanza
Garrabou Tornos, Glòria
author_role author
author2 Juárez Flores, Diana Luz
Morén Núñez, Constanza
Garrabou Tornos, Glòria
author2_role author
author
author
dc.subject.none.fl_str_mv Malalties neurodegeneratives
Autofàgia
Malaltia de Parkinson
Neurodegenerative Diseases
Autophagy
Parkinson's disease
topic Malalties neurodegeneratives
Autofàgia
Malaltia de Parkinson
Neurodegenerative Diseases
Autophagy
Parkinson's disease
description Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder worldwide affecting 2-3% of the population over 65 years. This prevalence is expected to rise as life expectancy increases and diagnostic and therapeutic protocols improve. PD encompasses a multitude of clinical, genetic, and molecular forms of the disease. Even though the mechanistic of the events leading to neurodegeneration remain largely unknown, some molecular hallmarks have been repeatedly reported in most patients and models of the disease. Neuroinflammation, protein misfolding, disrupted endoplasmic reticulum-mitochondria crosstalk, mitochondrial dysfunction and consequent bioenergetic failure, oxidative stress and autophagy deregulation, are amongst the most commonly described. Supporting these findings, numerous familial forms of PD are caused by mutations in genes that are crucial for mitochondrial and autophagy proper functioning. For instance, late and early onset PD associated to mutations in Leucine-rich repeat kinase 2 (LRRK2) and Parkin (PRKN) genes, responsible for the most frequent dominant and recessive inherited forms of PD, respectively, have emerged as promising examples of disease due to their established role in commanding bioenergetic and autophagic balance. Concomitantly, the development of animal and cell models to investigate the etiology of the disease, potential biomarkers and therapeutic approaches are being explored. One of the emerging approaches in this context is the use of patient's derived cells models, such as skin-derived fibroblasts that preserve the genetic background and some environmental cues of the patients. An increasing number of reports in these PD cell models postulate that deficient mitochondrial function and impaired autophagic flux may be determinant in PD accelerated nigral cell death in terms of limitation of cell energy supply and accumulation of obsolete and/or unfolded proteins or dysfunctional organelles. The reliance of neurons on mitochondrial oxidative metabolism and their post-mitotic nature, may explain their increased vulnerability to undergo degeneration upon mitochondrial challenges or autophagic insults. In this scenario, proper mitochondrial function and turnover through mitophagy, are gaining in strength as protective targets to prevent neurodegeneration, together with the use of patient-derived fibroblasts to further explore these events. These findings point out the presence of molecular damage beyond the central nervous system (CNS) and proffer patient-derived cell platforms to the clinical and scientific community, which enable the study of disease etiopathogenesis and therapeutic approaches focused on modifying the natural history of PD through, among others, the enhancement of mitochondrial function and autophagy.
publishDate 2019
dc.date.none.fl_str_mv 2019
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/175776
url https://hdl.handle.net/2445/175776
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a: https://doi.org/10.3389/fnins.2019.00894
Frontiers in Neuroscience, 2019, vol. 13
https://doi.org/10.3389/fnins.2019.00894
dc.rights.none.fl_str_mv cc-by (c) González Casacuberta, Ingrid et al., 2019
http://creativecommons.org/licenses/by/3.0/es
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc-by (c) González Casacuberta, Ingrid et al., 2019
http://creativecommons.org/licenses/by/3.0/es
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Frontiers Media
publisher.none.fl_str_mv Frontiers Media
dc.source.none.fl_str_mv Articles publicats en revistes (Medicina)
reponame:Dipòsit Digital de la UB
instname:Universidad de Barcelona
instname_str Universidad de Barcelona
reponame_str Dipòsit Digital de la UB
collection Dipòsit Digital de la UB
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15.300724

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