Mitochondrial dysfunction in Parkinson disease: evidence in mutant PARK2 fibroblasts

Zanellati, Maria Clara; Monti, Valentina; Barzaghi, Chiara; Reale, Chiara; Nardocci, Nardo; Albanese, Alberto; Valente, Enza Maria; Ghezzi, Daniele; Garavaglia, Barbara

doi:10.3389/fgene.2015.00078

Cited by 65 publications

(75 citation statements)

References 27 publications

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“…1B-D). Consistent with previous analyses on idiopathic PD 8 or Parkin mutant fibroblasts, 24 we did not observe any difference in basal or stimulated extracellular acidification rate in both glucose-or galactose-culturing conditions ( Supplementary Fig. 1E).…”

Section: Characterization Of Mitochondrial Function In Permitting Versupporting

confidence: 92%

Peripheral mitochondrial function correlates with clinical severity in idiopathic Parkinson's disease

et al. 2019

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Background Parkinson's disease is an intractable disorder with heterogeneous clinical presentation that may reflect different underlying pathogenic mechanisms. Surrogate indicators of pathogenic processes correlating with clinical measures may assist in better patient stratification. Mitochondrial function, which is impaired in and central to PD pathogenesis, may represent one such surrogate indicator. Methods Mitochondrial function was assessed by respirometry experiment in fibroblasts derived from idiopathic patients (n = 47) in normal conditions and in experimental settings that do not permit glycolysis and therefore force energy production through mitochondrial function. Respiratory parameters and clinical measures were correlated with bivariate analysis. Machine‐learning‐based classification and regression trees were used to classify patients on the basis of biochemical and clinical measures. The effects of mitochondrial respiration on α‐synuclein stress were assessed monitoring the protein phosphorylation in permitting versus restrictive glycolysis conditions. Results Bioenergetic properties in peripheral fibroblasts correlate with clinical measures in idiopathic patients, and the correlation is stronger with predominantly nondopaminergic signs. Bioenergetic analysis under metabolic stress, in which energy is produced solely by mitochondria, shows that patients’ fibroblasts can augment respiration, therefore indicating that mitochondrial defects are reversible. Forcing energy production through mitochondria, however, favors α‐synuclein stress in different cellular experimental systems. Machine‐learning‐based classification identified different groups of patients in which increasing disease severity parallels higher mitochondrial respiration. Conclusion The suppression of mitochondrial activity in PD may be an adaptive strategy to cope with concomitant pathogenic factors. Moreover, mitochondrial measures in fibroblasts are potential peripheral biomarkers to follow disease progression. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

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Section: Characterization Of Mitochondrial Function In Permitting Versupporting

confidence: 92%

Peripheral mitochondrial function correlates with clinical severity in idiopathic Parkinson's disease

et al. 2019

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“…In fibroblasts from patients that harbor PARK2 mutations, mitochondria are impaired, ATP levels are reduced and there is reduction in the membrane potential (Zanellati et al . ). Mutant mice with the substitution (D257A) in the amino acid located in exonuclease domain II of POLG, which reduces its ability to proofread, accumulates high levels of mtDNA deletions (Kujoth et al .…”

Section: Altered Mitochondrial Respiration In Pdmentioning

confidence: 97%

Mitochondrial dysfunction in Parkinson's disease

Bose

Beal

2016

Journal of Neurochemistry

675

482

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Parkinson's disease (PD) is the second most common neurodegenerative disease. About 2% of the population above the age of 60 is affected by the disease. The pathological hallmarks of the disease include the loss of dopaminergic neurons in the substantia nigra and the presence of Lewy bodies that are made of a-synuclein. Several theories have been suggested for the pathogenesis of PD, of which mitochondrial dysfunction plays a pivotal role in both sporadic and familial forms of the disease. Dysfunction of the mitochondria that is caused by bioenergetic defects, mutations in mitochondrial DNA, nuclear DNA gene mutations linked to mitochondria, and changes in dynamics of the mitochondria such fusion or fission, changes in size and morphology, alterations in trafficking or transport, altered movement of mitochondria, impairment of transcription, and the presence of mutated proteins associated with mitochondria are implicated in PD. In this review, we provide a detailed overview of the mechanisms that can cause mitochondrial dysfunction in PD. We bring to the forefront, new signaling pathways such as the retromer-trafficking pathway and its implication in the disease and also provide a brief overview of therapeutic strategies to improve mitochondrial defects in PD.

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“…Mitochondrial dysfunction and decreased energetic metabolism are consistently observed in skin fibroblasts from patients with PD. 144 This has been demonstrated in cultures from patients with parkin mutations 145,146 and SNCA triplication. 147 Enhanced vulnerability of skin fibroblasts in PARK6 to apoptosis induced by proteosomal stress has been reported.…”

Section: Skin Biopsies and Snca As Diagnostic Markers Of Pdmentioning

confidence: 94%

The Skin and Parkinson's Disease: Review of Clinical, Diagnostic, and Therapeutic Issues

Škorvánek

Bhatia

2016

Movement Disord Clin Pract

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Background: Parkinson's disease (PD) and the skin are related in a number of ways, including clinical abnormalities of the disease itself and skin-related side effects of dopaminergic medication, pumps, and surgical therapies. Recent advances in understanding the role of a-synuclein suggest skin biopsies as a potential diagnostic or even a premotor marker of PD. Methods: The PubMed database was searched for publications up to October 2015, and the current evidence on skin-related issues in PD was comprehensively summarized. Results: The evidence was summarized on the prevalence, etiology, and management of seborrheic dermatitis, sweating dysfunctions, bullous pemphigoid, and malignant melanoma, as well as therapy-related skin disorders, especially those observed in amantadine, rotigotine, apomorphine, and levodopa/carbidopa intestinal gel therapies and deep-brain stimulation. Skin biopsies evaluating the presence of a-synuclein, the density and morphology of cutaneous nerves, and skin fibroblast functions also are discussed. Conclusions: Skin disorders are a common manifestation of PD. However, the exact pathophysiology and prevalence of these disorders are not well understood, and more systematic research is needed in this regard. Peripheral tissue biopsies as a diagnostic marker of PD are an exciting avenue in future PD research, although multiple caveats and pending issues need to be solved before they can be used in routine clinical practice.Parkinson's disease (PD) is a progressive neurodegenerative disease characterized by the presence of multiple motor and nonmotor symptoms. Skin disorders, such as seborrheic dermatitis (SD) and hyperhidrosis, are well recognized and frequent -but often overlooked-nonmotor symptoms of PD; they have been associated with PD for nearly a century, since the first reports of seborrheic facies in PD by Krestin.1 Given the interest in biomarkers that precede the motor features of PD, it is worth noting that skin affection may precede the onset of typical motor symptoms by years. 2 Other skin disorders, such as malignant melanoma and bullous pemphigoid (BP), are significantly more prevalent in PD patients compared with the general population. 3,4 Recent advances in the understanding of the role of a-synuclein (SNCA) in the pathophysiology of PD, its prion-like mechanism of spreading, and findings of typical Lewy body pathology in the peripheral nervous system, suggest skin biopsies as a potential diagnostic marker of PD. Unlike the peripheral melanins produced in skin melanocytes, neuromelanin is produced in specific populations of catecholaminergic neurons in the brain. It is believed that neuromelanin interacts with transition metals, especially iron, and mediates intracellular oxidative mechanisms. This function seems to be compromised in PD, thus rendering pigmented neurons vulnerable to oxidative damage. 5 The skin can be affected by antiparkinsonian medication as well. Specific drug-delivery methods, such as skin patches, subcutaneous application of apomorphine, l...

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Mitochondrial dysfunction in Parkinson disease: evidence in mutant PARK2 fibroblasts

Cited by 65 publications

References 27 publications

Peripheral mitochondrial function correlates with clinical severity in idiopathic Parkinson's disease

Peripheral mitochondrial function correlates with clinical severity in idiopathic Parkinson's disease

Mitochondrial dysfunction in Parkinson's disease

The Skin and Parkinson's Disease: Review of Clinical, Diagnostic, and Therapeutic Issues

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