A constraint-based modelling approach to metabolic dysfunction in Parkinson's disease

Mao, Longfei; Nicolae, Averina; Oliveira, Miguel A. P.; He, Feng; Hachi, Siham; Fleming, Ronan M. T.

doi:10.1016/j.csbj.2015.08.002

Cited by 6 publications

(6 citation statements)

References 65 publications

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“…AMD is associated with mitochondrial dysfunction and energy deficiency [ 3 , 6 ]. Impaired cholesterol metabolism may contribute to formation of senile plaques and neurofibrillary tangles in Alzheimer’s disease [ 4 ], and metabolic dysregulation has been linked to Parkinson’s disease [ 5 ]. Mitochondrial dysfunction in neurodegenerative disease may result in impaired ATP production, and may also increase mitochondrial generation of reactive oxygen species or initiate mitochondrial apoptosis [ 23 ].…”

Section: Discussionmentioning

confidence: 99%

“…Accordingly, mitochondrial dysfunction has been linked to a litany of retinal diseases, including age-related macular degeneration, diabetic retinopathy, macular telangtasia and, potentially, retinal degenerations [ 3 ]. Further, a growing body of evidence suggests that neurodegenerative diseases of the brain and peripheral nervous system may also have a metabolic root [ 4 , 5 ]. It is therefore imperative to further the understanding of neuronal energy metabolism such that additional therapeutics targeting metabolic dysregulation can be developed.…”

Section: Introductionmentioning

confidence: 99%

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PPARα is essential for retinal lipid metabolism and neuronal survival

et al. 2017

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BackgroundPeroxisome proliferator activated receptor-alpha (PPARα) is a ubiquitously expressed nuclear receptor. The role of endogenous PPARα in retinal neuronal homeostasis is unknown. Retinal photoreceptors are the highest energy-consuming cells in the body, requiring abundant energy substrates. PPARα is a known regulator of lipid metabolism, and we hypothesized that it may regulate lipid use for oxidative phosphorylation in energetically demanding retinal neurons.ResultsWe found that endogenous PPARα is essential for the maintenance and survival of retinal neurons, with Pparα -/- mice developing retinal degeneration first detected at 8 weeks of age. Using extracellular flux analysis, we identified that PPARα mediates retinal utilization of lipids as an energy substrate, and that ablation of PPARα ultimately results in retinal bioenergetic deficiency and neurodegeneration. This may be due to PPARα regulation of lipid transporters, which facilitate the internalization of fatty acids into cell membranes and mitochondria for oxidation and ATP production.ConclusionWe identify an endogenous role for PPARα in retinal neuronal survival and lipid metabolism, and furthermore underscore the importance of fatty acid oxidation in photoreceptor survival. We also suggest PPARα as a putative therapeutic target for age-related macular degeneration, which may be due in part to decreased mitochondrial efficiency and subsequent energetic deficits.Electronic supplementary materialThe online version of this article (doi:10.1186/s12915-017-0451-x) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

PPARα is essential for retinal lipid metabolism and neuronal survival

et al. 2017

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“…To further examine these issues, we developed constraint-based metabolic models specific to naïve CD4 + T cells, Th1, Th2, and Th17 cells. Genome-scale constraint-based metabolic models include a structural representation of a cell’s entire biochemical reactions and help in computing biochemically feasible functional states 32 . These models consist of a stoichiometry matrix of biochemical reactions, exchange reactions (connecting cells internal metabolism with the environment), and additional constraints for upper and lower bounds for fluxes to be identified.…”

Section: Resultsmentioning

confidence: 99%

Integrative computational approach identifies drug targets in CD4+ T-cell-mediated immune disorders

et al. 2021

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CD4+ T cells provide adaptive immunity against pathogens and abnormal cells, and they are also associated with various immune-related diseases. CD4+ T cells’ metabolism is dysregulated in these pathologies and represents an opportunity for drug discovery and development. Genome-scale metabolic modeling offers an opportunity to accelerate drug discovery by providing high-quality information about possible target space in the context of a modeled disease. Here, we develop genome-scale models of naïve, Th1, Th2, and Th17 CD4+ T-cell subtypes to map metabolic perturbations in rheumatoid arthritis, multiple sclerosis, and primary biliary cholangitis. We subjected these models to in silico simulations for drug response analysis of existing FDA-approved drugs and compounds. Integration of disease-specific differentially expressed genes with altered reactions in response to metabolic perturbations identified 68 drug targets for the three autoimmune diseases. In vitro experimental validation, together with literature-based evidence, showed that modulation of fifty percent of identified drug targets suppressed CD4+ T cells, further increasing their potential impact as therapeutic interventions. Our approach can be generalized in the context of other diseases, and the metabolic models can be further used to dissect CD4+ T-cell metabolism.

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“…Still, large data sets that are being generated by applying especially ‘omics’ analysis methods to patient-derived cultures can inform in silico models of cellular function in response to stressors in PD. With regard to the human metabolome, a virtual database has already been generated ([ 125 ]; www.vmh.life ) and efforts are being made to extend this work to specific cell types in PD [ 126 ]. However, currently, these models do not consider disruptions due to environmental insults, which may at least partially stem from the fact that the landscape of chemicals relevant in the pathogenesis of PD is not well defined.…”

Section: Discussionmentioning

confidence: 99%

Molecular mechanisms defining penetrance of LRRK2-associated Parkinson’s disease

Trinh

Schymanski

Smajić

et al. 2022

Medizinische Genetik

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Mutations in Leucine-rich repeat kinase 2 (LRRK2) are the most frequent cause of dominantly inherited Parkinson’s disease (PD). LRRK2 mutations, among which p.G2019S is the most frequent, are inherited with reduced penetrance. Interestingly, the disease risk associated with LRRK2 G2019S can vary dramatically depending on the ethnic background of the carrier. While this would suggest a genetic component in the definition of LRRK2-PD penetrance, only few variants have been shown to modify the age at onset of patients harbouring LRRK2 mutations, and the exact cellular pathways controlling the transition from a healthy to a diseased state currently remain elusive. In light of this knowledge gap, recent studies also explored environmental and lifestyle factors as potential modifiers of LRRK2-PD. In this article, we (i) describe the clinical characteristics of LRRK2 mutation carriers, (ii) review known genes linked to LRRK2-PD onset and (iii) summarize the cellular functions of LRRK2 with particular emphasis on potential penetrance-related molecular mechanisms. This section covers LRRK2’s involvement in Rab GTPase and immune signalling as well as in the regulation of mitochondrial homeostasis and dynamics. Additionally, we explored the literature with regard to (iv) lifestyle and (v) environmental factors that may influence the penetrance of LRRK2 mutations, with a view towards further exposomics studies. Finally, based on this comprehensive overview, we propose potential future in vivo, in vitro and in silico studies that could provide a better understanding of the processes triggering PD in individuals with LRRK2 mutations.

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A constraint-based modelling approach to metabolic dysfunction in Parkinson's disease

Cited by 6 publications

References 65 publications

PPARα is essential for retinal lipid metabolism and neuronal survival

PPARα is essential for retinal lipid metabolism and neuronal survival

Integrative computational approach identifies drug targets in CD4+ T-cell-mediated immune disorders

Molecular mechanisms defining penetrance of LRRK2-associated Parkinson’s disease

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