Does Mitochondrial DNA Play a Role in Parkinson's Disease? A Review of Cybrid and Other Supportive Evidence

Swerdlow, Russell H.

doi:10.1089/ars.2011.3948

Cited by 34 publications

(40 citation statements)

References 166 publications

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“…Brain bioenergetic dysfunction is observed in several neurodegenerative diseases, and may contribute to their onset or progression (Swerdlow 2009, Swerdlow 2012b, Swerdlow 2012a). Because diet impacts bioenergetics, the ability of diet interventions to exacerbate or mitigate certain neurodegenerative disease states, at either a disease modifying or symptom level, is increasingly being considered (Swerdlow 2011, Swerdlow 2014).…”

Section: Introductionmentioning

confidence: 99%

Effect of one month duration ketogenic and non-ketogenic high fat diets on mouse brain bioenergetic infrastructure

Selfridge

Wilkins

Lezi

et al. 2014

J Bioenerg Biomembr

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Diet composition may affect energy metabolism in a tissue-specific manner. Using C57Bl/6J mice, we tested the effect of ketosis-inducing and non-inducing high fat diets on genes relevant to brain bioenergetic infrastructures, and on proteins that constitute and regulate that infrastructure. At the end of a one-month study period the two high fat diets appeared to differentially affect peripheral insulin signaling, but brain insulin signaling was not obviously altered. Some bioenergetic infrastructure parameters were similarly impacted by both high fat diets, while other parameters were only impacted by the ketogenic diet. For both diets, mRNA levels for CREB, PGC1α, and NRF2 increased while NRF1, TFAM, and COX4I1 mRNA levels decreased. PGC1β mRNA increased and TNFα mRNA decreased only with the ketogenic diet. Brain mtDNA levels fell in both the ketogenic and non-ketogenic high fat diet groups, although TOMM20 and COX4I1 protein levels were maintained, and mRNA and protein levels of the mtDNA-encoded COX2 subunit were also preserved. Overall, the pattern of changes observed in mice fed ketogenic and non-ketogenic high fat diets over a one month time period suggests these interventions enhance some aspects of the brain’s aerobic infrastructure, and may enhance mtDNA transcription efficiency. Further studies to determine which diet effects are due to changes in brain ketone body levels, fatty acid levels, glucose levels, altered brain insulin signaling, or other factors such as adipose tissue-associated hormones are indicated.

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Section: Introductionmentioning

confidence: 99%

Effect of one month duration ketogenic and non-ketogenic high fat diets on mouse brain bioenergetic infrastructure

Selfridge

Wilkins

Lezi

et al. 2014

J Bioenerg Biomembr

Self Cite

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“…Neuroblastoma cell lines such as SH-SY5Y cells have been used as a neuronal-like model to create transmitochondrial cybrids carrying deficient mitochondria from Parkinson’s or Alzheimer’s disease patients, showing that the mitochondrial defect was transferred to the cybrid cell lines [19–20]. …”

Section: Introductionmentioning

confidence: 99%

Metabolically induced heteroplasmy shifting and l-arginine treatment reduce the energetic defect in a neuronal-like model of MELAS

Desquiret-Dumas¹,

Guéguen²,

Barth³

et al. 2012

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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The m.3243A>G variant in the mitochondrial tRNALeu (UUR) gene is a common mitochondrial DNA (mtDNA) mutation. Phenotypic manifestations depend mainly on the heteroplasmy, i.e. the ratio of mutant to normal mtDNA copies. A high percentage of mutant mtDNA is associated with a severe, life-threatening neurological syndrome known as MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes). MELAS is described as a neurovascular disorder primarily affecting the brain and blood vessels, but the pathophysiology of the disease is poorly understood. We developed a series of cybrid cell lines at two different mutant loads: 70% and 100% in the nuclear background of a neuroblastoma cell line (SH-SY5Y). We investigated the impact of the mutation on the metabolism and mitochondrial respiratory chain activity of the cybrids. The m.3243A>G mitochondrial mutation induced a metabolic switch towards glycolysis in the neuronal cells and produced severe defects in respiratory chain assembly and activity. We used two strategies to compensate for the biochemical defects in the mutant cells: one consisted of lowering the glucose content in the culture medium, and the other involved the addition of L-arginine. The reduction of glucose significantly shifted the 100% mutant cells towards the wild-type, reaching a 90% mutant level and restoring respiratory chain complex assembly. The addition of L-arginine, a nitric oxide (NO) donor, improved complex I activity in the mutant cells in which the defective NO metabolism had led to a relative shortage of NO. Thus, metabolically induced heteroplasmy shifting and L-arginine therapy may constitute promising therapeutic strategies against MELAS.

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“…In this section, we suggest the hematopoietic stem cell niche as a site to consider. Research based on gene expression 18,25 , DNA methylation 27 , neuron-platelet cybrid 43,42,15 and bioenergetic 32 analyses supports the presence of the PD-state in circulating hematopoietic cells. Given the short lifespan of blood cells (days for platelets 54 and granulocytes 55 and weeks for lymphocytes, with the exception of memory cells 56 ) by comparison with the decade long timescale for the transmission of PD across the neuronal system 36,37,38 , the above signs of PD in blood point to circulating hematopoietic cells acquiring the PD-state at hematopoiesis, rather than after maturation.…”

Section: A Site Of Origin For the Pd-statementioning

confidence: 95%

“…Thus, the mtDNA of the cybrid cell is that of the platelet from the PD patient, while its nuclear DNA is that of the disease-free neuronal cell. Various PD characteristic alterations have been observed in PD cybrids, most prominently, inclusions that replicate the essential biochemical and structural features found in Lewy-bodies in the brain of PD patients 15,42,43 . The sufficiency of mtDNA to trigger the PD-state in a cell is supported by its ability to induce epigenetic modifications and to modulate gene-expression in nuclear DNA.…”

Section: The Propagation Of the Pd-statementioning

confidence: 97%

“…Whether with an initially external origin or endogenously generated, the theory that a misfolded, prion-like self-propagating form of alpha-synuclein is responsible for the disease is another major hypothesis currently under investigation 9,13 . More endogenous, aging-related perspectives of sporadic PD focus on the role of oxidative stress and mitochondrial damage, for which there is significant evidence in PD patients 14,15 . Finally, although the view of sporadic PD as an autoimmune disease is not typical, the aggravating contribution of the neuro-inflammatory response to the disease is commonly acknowledged 16,17 .…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

The universal non-neuronal nature of Parkinson's disease: A theory

Valente

Adilbayeva

Tokay

et al. 2016

Preprint

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Parkinson's disease (PD) is one of the most common neurodegenerative disorders, yet the etiology of the majority of its cases remains unknown. In this article, relevant published evidence is interpreted and integrated into a comprehensive hypothesis on the nature, origin and intercellular mode of propagation of sporadic PD. We propose to characterize sporadic PD as a pathological deviation in the global gene expression program of a cell: the PD expression-state, or PD-state for short. A universal cell-generic state, the PD-state deviation would be particularly damaging in a neuronal context, ultimately leading to neuron death and the ensuing observed clinical signs. We review why ageing associated accumulated damage caused by oxidative stress in mitochondria could be the trigger for a primordial cell to shift to the PD-state. We propose that hematopoietic cells could be the first to acquire the PD-state, at hematopoiesis, from the disruption in reactive oxygen species (ROS) homeostasis that arises with age in the hematopoietic stem-cell niche. We argue that cellular ageing is nevertheless unlikely to explain the shift to the PD-state of all the subsequently affected cells in a patient, thus indicating the existence of a distinct mechanism of cellular propagation of the PD-state. We highlight recently published findings on the inter-cellular exchange of mitochondrial DNA and the ability of mitochondrial DNA to modulate the cellular global gene expression state and propose this could form the basis for the inter-cellular transmission of the PD-state.

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Does Mitochondrial DNA Play a Role in Parkinson's Disease? A Review of Cybrid and Other Supportive Evidence

Cited by 34 publications

References 166 publications

Effect of one month duration ketogenic and non-ketogenic high fat diets on mouse brain bioenergetic infrastructure

Effect of one month duration ketogenic and non-ketogenic high fat diets on mouse brain bioenergetic infrastructure

Metabolically induced heteroplasmy shifting and l-arginine treatment reduce the energetic defect in a neuronal-like model of MELAS

The universal non-neuronal nature of Parkinson's disease: A theory

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