Transcriptional alterations in skin fibroblasts from Parkinson's disease patients with parkin mutations

González‐Casacuberta, Ingrid; Morén, Constanza; Juárez-Flores, Diana-Luz; Esteve‐Codina, Anna; Sierra, Cristina; Catalán-García, Marc; Guitart‐Mampel, Mariona; Tobías, Ester; Milisenda, José C.; Pont‐Sunyer, Claustre; Martı́, Marı́a José; Cardellach, Francesc; Tolosa, Eduard; Artuch, Rafael; Ezquerra, Mario; Fernández‐Santiago, Rubén; Garrabou, Glòria

doi:10.1016/j.neurobiolaging.2018.01.021

Cited by 14 publications

(17 citation statements)

References 108 publications

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“…Moreover, recent studies have described presence of whole expression changes in non-nervous tissues like blood from PD patients and also its derivates [2]. Recently, we have found large global gene expression changes in primary cultures of fibroblasts from PD patients carrying mutations in the Parkin gene ( PRKN ) [3] thus supporting a novel view of PD as a systemic disease that can also affect peripheral non-neural tissues. A possible interpretation is that there could exist intrinsic alterations related with the disease in each individual cell of the skin and potentially in any cell of the body, i.e.…”

mentioning

confidence: 84%

Parkinson’s disease as a systemic pathology

Ezquerra

Martí

Fernández‐Santiago

2019

Aging

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confidence: 84%

Parkinson’s disease as a systemic pathology

Ezquerra

Martí

Fernández‐Santiago

2019

Aging

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“…Our results suggest that an optimal mitochondrial bioenergetics, dynamics and autophagic function, and the capacity to adapt to challenging environments, play a role in the onset of clinically manifest PD due to LRRK2 mutations [4]. Current ongoing studies point out the importance of an optimal mitochondrial function necessary to achieve high ATP demands in response to an upregulation of anabolic cellular pathways that has been recently evidenced through transcriptomic and biochemical approaches in patients carrying PRKN mutation [5]. Strikingly, and in accordance to our findings, Y. Teves et al have described the differential morphological, mitochondrial and autophagic phenotype in fibroblasts obtained from idiopathic PD patients.…”

mentioning

confidence: 88%

Mitohormesis and autophagic balance in Parkinson disease

Juárez‐Flores

González‐Casacuberta

Garrabou

2019

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“…For instance, a great number of studies have reported α-synuclein deposits in many different peripheral tissues derived from PD patients (Tolosa and Vilas, 2015). On the other hand, many other alterations at molecular level including transcriptional changes, mitochondrial dysfunction and associated increased oxidative stress as well as autophagy deregulation have been described in PD-derived peripheral tissues such as muscle (Cardellach et al, 1993), blood cells including platelets and leukocytes (Haas et al, 1995; Muftuoglu et al, 2004; Mutez et al, 2014) and fibroblasts (Mortiboys et al, 2010; González-Casacuberta et al, 2018; Juarez-Flores et al, 2018), supporting the use of novel peripheral approaches.…”

Section: Models To Study Parkinson’s Diseasementioning

confidence: 99%

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

et al. 2019

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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.

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Transcriptional alterations in skin fibroblasts from Parkinson's disease patients with parkin mutations

Cited by 14 publications

References 108 publications

Parkinson’s disease as a systemic pathology

Parkinson’s disease as a systemic pathology

Mitohormesis and autophagic balance in Parkinson disease

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

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