Lactate has been long thought of as a dead-end waste product of glycolysis. In the brain,
recent evidence has revealed a key role of L-lactate creating a paradigm-shift in our
understanding of the neuronal energy metabolism. The Astrocyte neuron lactate shuttle
(ANLS) model, has shown L-Lactate as the main energy substrate delivered by astrocytes
to neurons to sustain neuronal oxidative metabolism. This metabolic coupling is an
essential mechanism for long-term memory formation. Experimental evidence indicates
that the role of lactate in cognitive function is not limited to being a neuronal metabolic
substrate, but rather it is also an important signaling molecule for synaptic plasticity. One
of the new emerging roles of lactate is its effect on gene expression levels; however, our
current understanding of the mechanism of lactate effect on gene expression is
rudimentary. Here, I investigate the role of lactate as an epigenetic modulator in neuronal
cultures. First, I explored the effect of lactate on the transcriptome and methylome of the
neuronal cells using primary neuronal cell culture models. Our results reveal a significant
role for lactate in inducing neuronal cell differentiation. Following, I characterized a
neuroblastoma cell line as our neuronal differentiation cell model and assessed its
metabolic features relative to other immortal cell lines. Further, using the cell line in vitro
model, I looked into the metabolic reprograming that occurs in parallel with the first
indications of differentiation, focusing on lactate production rates. Subsequently, I
investigated the role of lactate in differentiation through transcriptomic analysis. We show
that lactate induced histone acetylation and promoted expression of dopaminergic markers,
with a stronger effect of D-lactate over L-lactate. Further studies to establish potential
linkages between those two pathways will enhance our understanding of the effect of
lactate.
| Identifer | oai:union.ndltd.org:kaust.edu.sa/oai:repository.kaust.edu.sa:10754/663537 |
| Date | 11 1900 |
| Creators | Darwish, Manar M. |
| Contributors | Magistretti, Pierre J., Biological and Environmental Sciences and Engineering (BESE) Division, Merzaban, Jasmeen, Aranda, Manuel, Gräff, Johannes, Fiumelli, Hubert |
| Source Sets | King Abdullah University of Science and Technology |
| Language | English |
| Detected Language | English |
| Type | Dissertation |
| Rights | 2021-06-14, At the time of archiving, the student author of this dissertation opted to temporarily restrict access to it. The full text of this dissertation will become available to the public after the expiration of the embargo on 2021-06-14. |
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