The unresolved role of mitochondrial DNA in Parkinson's disease: An overview of published studies, their limitations, and future prospects

Müller-Nedebock, Amica Corda; Brennan, Rebecca R.; Venter, Marianne; Pienaar, Ilse S.; Westhuizen, Francois H. van der; Elson, Joanna L.; Ross, Owen A.; Bardien, Soraya

doi:10.1016/j.neuint.2019.104495

Cited by 26 publications

(22 citation statements)

References 173 publications

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“…Later, a number of genes associated with familial forms of PD were identified to play a role in the maintenance of mitochondrial function, further suggesting its involvement in PD pathogenesis [1, 52]. Moreover, mitochondrial DNA (mtDNA) variations and depletion in PD have been extensively investigated, although without definitive conclusions [48]. Notably, higher levels of mtDNA deletions in SNpc of both PD and aged brains have been reported [9, 40], and reduced mtDNA copy number has been suggested as a biomarker of PD [19, 54].…”

Section: Introductionmentioning

confidence: 99%

Cellular alterations identified in pluripotent stem cell-derived midbrain spheroids generated from a female patient with progressive external ophthalmoplegia and parkinsonism who carries a novel variation (p.Q811R) in the POLG1 gene

Chumarina

Russ

Azevedo

et al. 2019

acta neuropathol commun

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Variations in the POLG1 gene encoding the catalytic subunit of the mitochondrial DNA polymerase gamma, have recently been associated with Parkinson's disease (PD), especially in patients diagnosed with progressive external ophthalmoplegia (PEO). However, the majority of the studies reporting this association mainly focused on the genetic identification of the variation in POLG1 in PD patient primary cells, and determination of mitochondrial DNA copy number, providing little information about the cellular alterations existing in patient brain cells, in particular dopaminergic neurons. Therefore, through the use of induced pluripotent stem cells (iPSCs), we assessed cellular alterations in novel p.Q811R POLG1 (POLG1 Q811R) variant midbrain dopaminergic neuron-containing spheroids (MDNS) from a female patient who developed early-onset PD, and compared them to cultures derived from a healthy control of the same gender. Both POLG1 variant and control MDNS contained functional midbrain regionalized TH/FOXA2-positive dopaminergic neurons, capable of releasing dopamine. Western blot analysis identified the presence of high molecular weight oligomeric alpha-synuclein in POLG1 Q811R MDNS compared to control cultures. In order to assess POLG1 Q811R-related cellular alterations within the MDNS, we applied massspectrometry based quantitative proteomic analysis. In total, 6749 proteins were identified, with 61 significantly differentially expressed between POLG1 Q811R and control samples. Pro-and anti-inflammatory signaling and pathways involved in energy metabolism were altered. Notably, increased glycolysis in POLG1 Q811R MDNS was suggested by the increase in PFKM and LDHA levels and confirmed using functional analysis of glycolytic rate and oxygen consumption levels. Our results validate the use of iPSCs to assess cellular alterations in relation to PD pathogenesis, in a unique PD patient carrying a novel p.Q811R variation in POLG1, and identify several altered pathways that may be relevant to PD pathogenesis.

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Section: Introductionmentioning

confidence: 99%

Cellular alterations identified in pluripotent stem cell-derived midbrain spheroids generated from a female patient with progressive external ophthalmoplegia and parkinsonism who carries a novel variation (p.Q811R) in the POLG1 gene

Chumarina

Russ

Azevedo

et al. 2019

acta neuropathol commun

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“…Convincing evidence exists that mtDNA is involved in the mitochondrial dysfunction in Parkinson’s disease. However, it still remains unclear, whether numerous mtDNA damages (oxidation, deletions, mutations, and heteroplasmy) described in the literature are the cause or consequence of PD [ 12 , 164 , 165 ]. On the one hand, the analysis of human (including postmortem brain) tissue samples demonstrating various types of mtDNA damage suggests that the recognized changes may be attributed to the final outcome of the disease.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial Dysfunction in Parkinson’s Disease: Focus on Mitochondrial DNA

et al. 2020

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Mitochondria, the energy stations of the cell, are the only extranuclear organelles, containing their own (mitochondrial) DNA (mtDNA) and the protein synthesizing machinery. The location of mtDNA in close proximity to the oxidative phosphorylation system of the inner mitochondrial membrane, the main source of reactive oxygen species (ROS), is an important factor responsible for its much higher mutation rate than nuclear DNA. Being more vulnerable to damage than nuclear DNA, mtDNA accumulates mutations, crucial for the development of mitochondrial dysfunction playing a key role in the pathogenesis of various diseases. Good evidence exists that some mtDNA mutations are associated with increased risk of Parkinson’s disease (PD), the movement disorder resulted from the degenerative loss of dopaminergic neurons of substantia nigra. Although their direct impact on mitochondrial function/dysfunction needs further investigation, results of various studies performed using cells isolated from PD patients or their mitochondria (cybrids) suggest their functional importance. Studies involving mtDNA mutator mice also demonstrated the importance of mtDNA deletions, which could also originate from abnormalities induced by mutations in nuclear encoded proteins needed for mtDNA replication (e.g., polymerase γ). However, proteomic studies revealed only a few mitochondrial proteins encoded by mtDNA which were downregulated in various PD models. This suggests nuclear suppression of the mitochondrial defects, which obviously involve cross-talk between nuclear and mitochondrial genomes for maintenance of mitochondrial functioning.

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“…They describe mutations in mitochondrial DNA and genes associated with the immune system or with dopamine metabolism. All pathways analysed in Polish populations are set out in Table 2 [57,58,[60][61][62][63][64][65][66][67][68][69][70][71][72][73][74][75][76][77][78].…”

Section: Other Genetic Analysis In Polandmentioning

confidence: 99%

Genetics of Parkinson’s disease in the Polish population

Milanowski

Ross

Friedman

et al. 2021

Neurol Neurochir Pol.

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Introduction. Genetic forms of Parkinson's disease (PD) often cluster in different ethnic groups and may present with recognisable unique clinical manifestations. Our aim was to summarise the current state of knowledge regarding the genetic causes of PD and describe the first Polish patient with SNCA duplication.Methodology. We searched the electronic database, PubMed, for studies between January 1995 and June 2020 that evaluated genetics in Polish patients with PD, using the search terms 'Parkinson's disease, 'Polish' , 'genetics' , 'mutations' , and 'variants' .Results. In total, 73 publications were included in the review; 11 genes responsible for monogenic forms and 19 risk factor genes have been analysed in the Polish population. Pathogenic variants were reported in four monogenic genes (LRRK2, PRKN, PINK1, and SNCA). Eight genes were associated with PD risk in the Polish population (GBA, TFAM, NFE2L2, MMP12, HLA-DRA, COMT, MAOB, and DBH). Multiplex ligation-dependent probe amplification and Sanger sequencing in PRKN, PINK1, DJ1, LRRK2, and SNCA revealed SNCA duplication in a 43-year-old Polish patient with PD examined by movement disorder specialists. Conclusion.Only a limited number of positive results have been reported in genes previously associated with PD in the Polish population. In the era of personalised medicine, it is important to report on genetic findings in specific populations.

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The unresolved role of mitochondrial DNA in Parkinson's disease: An overview of published studies, their limitations, and future prospects

Abstract: Soraya (2019) The unresolved role of mitochondrial DNA in Parkinson's disease: an overview of published studies, their limitations, and future prospects. Neurochemistry International.

Cited by 26 publications

References 173 publications

Cellular alterations identified in pluripotent stem cell-derived midbrain spheroids generated from a female patient with progressive external ophthalmoplegia and parkinsonism who carries a novel variation (p.Q811R) in the POLG1 gene

Cellular alterations identified in pluripotent stem cell-derived midbrain spheroids generated from a female patient with progressive external ophthalmoplegia and parkinsonism who carries a novel variation (p.Q811R) in the POLG1 gene

Mitochondrial Dysfunction in Parkinson’s Disease: Focus on Mitochondrial DNA

Genetics of Parkinson’s disease in the Polish population

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