Mitochondrial abnormalities in Parkinson's disease and Alzheimer's disease: can mitochondria be targeted therapeutically?

MacDonald, Robert C.; Barnes, Katy; Hastings, Christopher; Mortiboys, Heather

doi:10.1042/bst20170501

Cited by 142 publications

(89 citation statements)

References 206 publications

(259 reference statements)

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“…Previous studies have shown an increase in ROS in some PRKN mutant patient neurons but not in others and have measured total cellular ROS rather than mitochondrial specific ROS which could explain why the data we present here is more consistent across the group of patients. Targeting mitochondrial dysfunction for a potential therapeutic to slow or stop disease progression is an attractive option with many mitochondrial targeted therapeutics shown to be effective in various models of PD (recently reviewed 2,46 ). Different therapeutic strategies are being developed; some primarily acting to boost energy deficits whilst others are targeting ROS production.…”

Section: Discussionmentioning

confidence: 99%

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Oxidative switch drives mitophagy defects in dopaminergic parkin mutant patient neurons

Schwartzentruber

Boschian

Lopes

et al. 2020

Sci Rep

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Mutations in PRKN are the most common cause of early onset Parkinson’s disease. Parkin is an E3 ubiquitin ligase, functioning in mitophagy. Mitochondrial abnormalities are present in PRKN mutant models. Patient derived neurons are a promising model in which to study pathogenic mechanisms and therapeutic targets. Here we generate induced neuronal progenitor cells from PRKN mutant patient fibroblasts with a high dopaminergic neuron yield. We reveal changing mitochondrial phenotypes as neurons undergo a metabolic switch during differentiation. Fibroblasts from 4 controls and 4 PRKN mutant patients were transformed into induced neuronal progenitor cells and subsequently differentiated into dopaminergic neurons. Mitochondrial morphology, function and mitophagy were evaluated using live cell fluorescent imaging, cellular ATP and reactive oxygen species production quantification. Direct conversion of control and PRKN mutant patient fibroblasts results in induced neuronal progenitor and their differentiation yields high percentage of dopaminergic neurons. We were able to observe changing mitochondrial phenotypes as neurons undergo a metabolic switch during differentiation. Our results show that when pre-neurons are glycolytic early in differentiation mitophagy is unimpaired by PRKN deficiency. However as neurons become oxidative phosphorylation dependent, mitophagy is severely impaired in the PRKN mutant patient neurons. These changes correlate with changes in mitochondrial function and morphology; resulting in lower neuron yield and altered neuronal morphology. Induced neuronal progenitor cell conversion can produce a high yield of dopaminergic neurons. The mitochondrial phenotype, including mitophagy status, is highly dependent on the metabolic status of the cell. Only when neurons are oxidative phosphorylation reliant the extent of mitochondrial abnormalities are identified. These data provide insight into cell specific effects of PRKN mutations, in particular in relation to mitophagy dependent disease phenotypes and provide avenues for alternative therapeutic approaches.

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Section: Discussionmentioning

confidence: 99%

“…Parkin is an E3 ubiquitin ligase and functions in the mitophagy pathway 1 . Mitochondrial dysfunction is well established in both familial and sporadic forms of PD (recently reviewed 2 ). Mitochondrial abnormalities are present in both PRKN null Drosophila 3 and mice 4 .…”

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confidence: 99%

Oxidative switch drives mitophagy defects in dopaminergic parkin mutant patient neurons

Schwartzentruber

Boschian

Lopes

et al. 2020

Sci Rep

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“…85,86 and the effects appear to be driven by increased neuronal apoptosis. 85 Given the well-established role of mitochondrial dysfunction in AD (reviewed in [87][88][89] [91][92][93] Attention-Deficit/Hyperactivity Disorder (ADHD), 94 and intellectual disabilities 95 through multiple protein function and regulatory mechanisms. It is downregulated in the hippocampus of AD patients, possibly through increased expression of the transcription factor Storkhead box 1A.…”

Section: Discussionmentioning

confidence: 99%

Genome‐wide association study of rate of cognitive decline in Alzheimer's disease patients identifies novel genes and pathways

Sherva

Gross

Mukherjee

et al. 2020

Alzheimer's & Dementia

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Introduction Variability exists in the disease trajectories of Alzheimer's disease (AD) patients. We performed a genome‐wide association study to examine rate of cognitive decline (ROD) in patients with AD. Methods We tested for interactions between genetic variants and time since diagnosis to predict the ROD of a composite cognitive score in 3946 AD cases and performed pathway analysis on the top genes. Results Suggestive associations (P < 1.0 × 10−6) were observed on chromosome 15 in DNA polymerase‐γ (rs3176205, P = 1.11 × 10−7), chromosome 7 (rs60465337,P = 4.06 × 10−7) in contactin‐associated protein‐2, in RP11‐384F7.1 on chromosome 3 (rs28853947, P = 5.93 × 10−7), family with sequence similarity 214 member‐A on chromosome 15 (rs2899492, P = 5.94 × 10−7), and intergenic regions on chromosomes 16 (rs4949142, P = 4.02 × 10−7) and 4 (rs1304013, P = 7.73 × 10−7). Significant pathways involving neuronal development and function, apoptosis, memory, and inflammation were identified. Discussion Pathways related to AD, intelligence, and neurological function determine AD progression, while previously identified AD risk variants, including the apolipoprotein (APOE) ε4 and ε2 variants, do not have a major impact.

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“…Several compounds that target the mitochondrial alterations found in AD such as Mito Q, Skulachev (SkQ1), melatonin, and Sezto-Shiller (SS) tetrapeptide SS31 reduce the neurodegenerative characteristics of mouse models of this disorder and are good candidates to be tested in clinical trials [383].…”

Section: Therapies Targeting Different Pathways Implicated In Ad Pathmentioning

confidence: 99%

Signalling Pathways Implicated in Alzheimer′s Disease Neurodegeneration in Individuals with and without Down Syndrome

Martı́nez-Cué

Rueda

2020

IJMS

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Down syndrome (DS), the most common cause of intellectual disability of genetic origin, is characterized by alterations in central nervous system morphology and function that appear from early prenatal stages. However, by the fourth decade of life, all individuals with DS develop neuropathology identical to that found in sporadic Alzheimer’s disease (AD), including the development of amyloid plaques and neurofibrillary tangles due to hyperphosphorylation of tau protein, loss of neurons and synapses, reduced neurogenesis, enhanced oxidative stress, and mitochondrial dysfunction and neuroinflammation. It has been proposed that DS could be a useful model for studying the etiopathology of AD and to search for therapeutic targets. There is increasing evidence that the neuropathological events associated with AD are interrelated and that many of them not only are implicated in the onset of this pathology but are also a consequence of other alterations. Thus, a feedback mechanism exists between them. In this review, we summarize the signalling pathways implicated in each of the main neuropathological aspects of AD in individuals with and without DS as well as the interrelation of these pathways.

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Mitochondrial abnormalities in Parkinson's disease and Alzheimer's disease: can mitochondria be targeted therapeutically?

Cited by 142 publications

References 206 publications

Oxidative switch drives mitophagy defects in dopaminergic parkin mutant patient neurons

Oxidative switch drives mitophagy defects in dopaminergic parkin mutant patient neurons

Genome‐wide association study of rate of cognitive decline in Alzheimer's disease patients identifies novel genes and pathways

Signalling Pathways Implicated in Alzheimer′s Disease Neurodegeneration in Individuals with and without Down Syndrome

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