Role of mtDNA disturbances in the pathogenesis of Alzheimer’s and Parkinson’s disease

Antonyová, Veronika; Kejík, Zdeněk; Brogyányi, Tereza; Kaplánek, Robert; Pajková, Martina; Talianová, Veronika; Hromádka, Róbert; Masařík, Michal; Sýkora, David; Mikšátková, Lucie; Martásek, Pavel; Jakubek, Milan

doi:10.1016/j.dnarep.2020.102871

Cited by 33 publications

(22 citation statements)

References 155 publications

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“…Mitochondrial dysfunction, such as reduced activity of mitochondrial electron transport chain complex I, mutations in mitochondrial quality control genes, and mtDNA disturbances has been implicated in the pathogenesis of PD ( Bose and Beal, 2016 ; Matheoud et al, 2016 ; Antonyová et al, 2020 ). Mitochondria are also key regulators of the NLRP3 inflammasome, with mitochondrial dysfunction resulting in NLRP3 assembly and activation ( Zhou et al, 2011 ; Elliott et al, 2018 ).…”

Section: Parkinson’s Diseasementioning

confidence: 99%

Neurodegenerative Disease and the NLRP3 Inflammasome

et al. 2021

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The prevalence of neurodegenerative disease has increased significantly in recent years, and with a rapidly aging global population, this trend is expected to continue. These diseases are characterised by a progressive neuronal loss in the brain or peripheral nervous system, and generally involve protein aggregation, as well as metabolic abnormalities and immune dysregulation. Although the vast majority of neurodegeneration is idiopathic, there are many known genetic and environmental triggers. In the past decade, research exploring low-grade systemic inflammation and its impact on the development and progression of neurodegenerative disease has increased. A particular research focus has been whether systemic inflammation arises only as a secondary effect of disease or is also a cause of pathology. The inflammasomes, and more specifically the NLRP3 inflammasome, a crucial component of the innate immune system, is usually activated in response to infection or tissue damage. Dysregulation of the NLRP3 inflammasome has been implicated in the progression of several neurodegenerative disorders, such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, and prion diseases. This review aims to summarise current literature on the role of the NLRP3 inflammasome in the pathogenesis of neurodegenerative diseases, and recent work investigating NLRP3 inflammasome inhibition as a potential future therapy.

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Section: Parkinson’s Diseasementioning

confidence: 99%

Neurodegenerative Disease and the NLRP3 Inflammasome

et al. 2021

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“…Currently, there is an increasing interest in the possibility of mtDNA variants predisposing to idiopathic PD [ 221 , 222 , 223 ]. Several studies have suggested an association of SNPs in mitochondrial genes with an enhanced risk for PD, such as 4216T>C in MT-ND1 [ 224 ], 5460G>A in MT-ND2 , as well as 4336T>C [ 225 , 226 ] and 4336A>G in MT-TQ [ 227 ].…”

Section: Mitochondrial Genetics and Epigenetics In Parkinson’s Diseasementioning

confidence: 99%

“…Dysfunctional mitochondria are also related to monogenic forms of PD: genetic methods have identified variants in mitophagy regulatory genes—e.g., PINK1 (PTEN-induced putative protein kinase 1), Parkin ( PRKN , parkin RBR E3 ubiquitin protein ligase) and DJ-1 (protein deglycase DJ-1)—as hereditary factors of PD etiology, being associated with early-onset autosomal recessive PD (age less than 45 years) through alterations in mitophagy [ 233 , 234 ]. In order to maintain mitochondrial homeostasis in the nervous system, mitophagy (the process of autophagic degradation of damaged mitochondria) may take place, mainly through the PINK1/Parkin pathway [ 223 , 235 ]. Thus, considering mitophagy is part of mitochondrial quality control, variants in genes related to this mechanism may impair the elimination of dysfunctional mitochondria in the brain of PD patients [ 236 ].…”

Section: Mitochondrial Genetics and Epigenetics In Parkinson’s Diseasementioning

confidence: 99%

Nuclear and Mitochondrial Genome, Epigenome and Gut Microbiome: Emerging Molecular Biomarkers for Parkinson’s Disease

Cabral

Schaan

Cavalcante

et al. 2021

IJMS

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Background: Parkinson’s disease (PD) is currently the second most common neurodegenerative disorder, burdening about 10 million elderly individuals worldwide. The multifactorial nature of PD poses a difficult obstacle for understanding the mechanisms involved in its onset and progression. Currently, diagnosis depends on the appearance of clinical signs, some of which are shared among various neurologic disorders, hindering early diagnosis. There are no effective tools to prevent PD onset, detect the disease in early stages or accurately report the risk of disease progression. Hence, there is an increasing demand for biomarkers that may identify disease onset and progression, as treatment-based medicine may not be the best approach for PD. Over the last few decades, the search for molecular markers to predict susceptibility, aid in accurate diagnosis and evaluate the progress of PD have intensified, but strategies aimed to improve individualized patient care have not yet been established. Conclusions: Genomic variation, regulation by epigenomic mechanisms, as well as the influence of the host gut microbiome seem to have a crucial role in the onset and progress of PD, thus are considered potential biomarkers. As such, the human nuclear and mitochondrial genome, epigenome, and the host gut microbiome might be the key elements to the rise of personalized medicine for PD patients.

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“…Indeed, it has been demonstrated that environmental exposures, contributing to the onset of new mutations or oxidative damages or modulating epigenetic features of mtDNA, strongly impact mitochondrial health. In the light of this evidence, mtDNA depletion and malfunction have been implicated in cancer [ 62 , 63 ], metabolic and cardiovascular diseases [ 43 , 64 , 65 , 66 , 67 ], aging [ 68 ], and many human multifactorial disorders, including neurodegeneration [ 69 , 70 ].…”

Section: Mitochondrial Dna: From Genetics To Epigeneticsmentioning

confidence: 99%

Mitochondrial DNA and Neurodegeneration: Any Role for Dietary Antioxidants?

Bordoni

Gabbianelli

2020

Antioxidants

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The maintenance of the mitochondrial function is essential in preventing and counteracting neurodegeneration. In particular, mitochondria of neuronal cells play a pivotal role in sustaining the high energetic metabolism of these cells and are especially prone to oxidative damage. Since overproduction of reactive oxygen species (ROS) is involved in the pathogenesis of neurodegeneration, dietary antioxidants have been suggested to counteract the detrimental effects of ROS and to preserve the mitochondrial function, thus slowing the progression and limiting the extent of neuronal cell loss in neurodegenerative disorders. In addition to their role in the redox-system homeostasis, mitochondria are unique organelles in that they contain their own genome (mtDNA), which acts at the interface between environmental exposures and the molecular triggers of neurodegeneration. Indeed, it has been demonstrated that mtDNA (including both genetics and, from recent evidence, epigenetics) might play relevant roles in modulating the risk for neurodegenerative disorders. This mini-review describes the link between the mitochondrial genome and cellular oxidative status, with a particular focus on neurodegeneration; moreover, it provides an overview on potential beneficial effects of antioxidants in preserving mitochondrial functions through the protection of mtDNA.

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Role of mtDNA disturbances in the pathogenesis of Alzheimer’s and Parkinson’s disease

Cited by 33 publications

References 155 publications

Neurodegenerative Disease and the NLRP3 Inflammasome

Neurodegenerative Disease and the NLRP3 Inflammasome

Nuclear and Mitochondrial Genome, Epigenome and Gut Microbiome: Emerging Molecular Biomarkers for Parkinson’s Disease

Mitochondrial DNA and Neurodegeneration: Any Role for Dietary Antioxidants?

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