ArticlePloS one2013
Metabolic states following accumulation of intracellular aggregates: implications for neurodegenerative diseases.
Article in PloS one, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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Who cites it
9 citing papers in PubMed, 22 citations in OpenAlex.
- Tau-targeting therapies for Alzheimer disease: current status and future directions.Nature reviews. Neurology · 2023Review
- Tau-targeting therapies for Alzheimer disease.Nature reviews. Neurology · 2018Review
- Metabolic network modeling with model organisms.Current opinion in chemical biology · 2017Review
- Computational Flux Balance Analysis Predicts that Stimulation of Energy Metabolism in Astrocytes and their Metabolic Interactions with Neurons Depend on Uptake of KNeurochemical research · 2017Article
- Mevalonate Pathway Regulates Cell Size Homeostasis and Proteostasis through Autophagy.Cell reports · 2015Article
- Proteome response at the edge of protein aggregation.Open biology · 2015Article
- Transcriptional and metabolic adaptation of human neurons to the mitochondrial toxicant MPP(+).Cell death & disease · 2014Article
- Structure and mechanism of action of tau aggregation inhibitors.Current Alzheimer research · 2014Review
- Glycolysis in patients with age-related macular degeneration.The open ophthalmology journal · 2014Article
Corrections and comments
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Authors and funding
1 author at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The formation of intracellular aggregates is a common etiology of several neurodegenerative diseases. Mitochondrial defects and oxidative stress has been pointed as the major mechanistic links between the accumulation of intracellular aggregates and cell death. In this work we propose a "metabolic cell death by overcrowding" as an alternative hypothesis. Using a model of neuron metabolism, we predict that as the concentration of protein aggregates increases the neurons transit through three different metabolic phases. The first phase (0-6 mM) corresponds with the normal neuron state, where the neuronal activity is sustained by the oxidative phosphorylation of lactate. The second phase (6-8.6 mM) is characterized by a mixed utilization of lactate and glucose as energy substrates and a switch from ammonia uptake to ammonia release by neurons. In the third phase (8.6-9.3 mM) neurons are predicted to support their energy demands from glycolysis and an alternative pathway for energy generation, involving reactions from serine synthesis, one carbon metabolism and the glycine cleavage system. The model also predicts a decrease in the maximum neuronal capacity for energy generation with increasing the concentration of protein aggregates. Ultimately this maximum capacity becomes zero when the protein aggregates reach a concentration of about 9.3 mM, predicting the cessation of neuronal activity.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.