To summarize: Studies reveal a novel mechanism in locus coeruleus neurons caused by deletion of the mitochondrial enzyme GPT2, which is implicated in the development and progression of neurodegenerative diseases.
resource: Brown University
Doctors and scientists already know that the locus coeruleus is one of the first brain regions to degenerate in Alzheimer’s and Parkinson’s diseases. But why the field is so fragile is less known.
While continuing to explore a rare neurogenetic disorder, a team of Brown University researchers has discovered an explanation for this important question.
in the magazine disease neurobiologythe researchers report a novel mechanism of degeneration of locus coeruleus neurons caused by the loss of the mitochondrial enzyme GPT2, which is implicated in the neurological disease of interest to the researchers.
“These findings represent a new direction for research into this very important part of the brain,” said study author Dr. Eric Morrow, professor of biology, neuroscience, psychiatry and human behavior at the Warren Alpert School of Medicine and director of Brown University . Center for Translational Neuroscience.
Located in the brainstem, the locus coeruleus is a key region that is the primary source of neurons that deliver the neurotransmitter norepinephrine through projections throughout the brain. Norepinephrine is a common drug target for the treatment of many diseases, Morrow said.
The locus coeruleus is involved in a variety of cognitive processes, such as attention, learning, mood, wakefulness, and sleep. The death of neurons in this part of the brain has also been linked to cognitive diseases such as Alzheimer’s and Parkinson’s.
In recent years, the locus coeruleus has become a broad and intense area of research interest, Morrow said. However, his team didn’t initially try to study this part of the brain in experiments.
“That’s one of the things that makes this discovery so exciting,” Morrow said. “This was a completely accidental discovery that, frankly, could have been missed. It’s an example of how research focused on genetic information can teach us lessons about the brain that we couldn’t have foreseen before.”
The team, including Brown neuroscience graduate student Ozan Baytas, has been studying how a specific genetic mutation is linked to a rare neurogenetic disorder called GPT2 deficiency — a genetic syndrome first reported by Morrow’s lab in 2016 sign.
The gene of interest is called GPT2 (glutamate pyruvate transaminase 2), and it produces an enzyme critical to the metabolic pathways of mitochondria, the energy center of the cell.
After introducing mutations into the metabolic genes of laboratory mice to study GPT2 deficiency, the researchers found that this loss of the mitochondrial enzyme caused the locus coeruleus to degenerate relatively early and selectively in the mice’s life cycle.
GPT2 enzymes regulate neuronal growth by replenishing tricarboxylic acid cycle intermediates and regulating amino acid metabolism.
In mice without the GPT2 enzyme, the researchers observed early loss of neurons in the locus coeruleus, as well as other signs of degeneration, such as insufficient protein synthesis and delayed cell growth.
A specific part of this work involves the electrophysiology of neurons. The experiments were conducted in the lab of co-author Julie Kaul, who was then at Brown University and is now a professor of psychiatry and behavioral sciences at Stanford University.
“Our findings suggest that altered metabolism may be the initial driver of neurodegeneration in the locus coeruleus,” said lead study author Baytas.
“Identifying the exact cause of this degeneration may shed light on the mechanisms of coeruleus that we can correct or better prevent to stop dementia and related behavioral conditions.
“Our findings in a mouse model of neurometabolic disease open up new prospects for locus coeruleus neurodegeneration and encourage further investigation of the metabolic susceptibility of these neurons.”
Because of the focus on the locus coeruleus in drug therapy development, Morrow said the discovery of early damage to this brain region will be of interest to a broad spectrum of the neuroscience and neuropsychiatry communities.
He added that the hope is that these studies will eventually lead to therapeutic targets for Alzheimer’s disease and other neurodegenerative diseases.
About this neurodegenerative disease research news
author: News office
resource: Brown University
touch: Press Office – Brown University
picture: Image via Brown University
Original research: Open access.
“Deletion of the mitochondrial enzyme GPT2 causes early neurodegeneration in the locus coeruleus” by Ozan Baytas et al. disease neurobiology
Deletion of the mitochondrial enzyme GPT2 causes early neurodegeneration in the locus coeruleus
The locus coeruleus (LC) is one of the first brain regions to degenerate in Alzheimer’s disease and Parkinson’s disease; however, the underlying cause of LC neuronal vulnerability remains unclear.
Here, we report a novel mechanism of LC neuronal degeneration caused by loss of the mitochondrial enzyme glutamate pyruvate transaminase 2 (GPT2). GPT2 deficiency is a newly discovered neurometabolic disorder in children.
GPT2 enzymes regulate cell growth by replenishing tricarboxylic acid (TCA) cycle intermediates and regulating amino acid metabolism.exist Gpt2-In null mice, we observed an early loss of tyrosine hydroxylase (TH)-positive neurons in the LC and reduced cell body size at postnatal day 18. Gpt2-Null LC showed selective positive Fluoro-Jade C staining.
In LC, neuronal loss is accompanied by selective, marked microgliosis and astrogliosis. We observed decreased noradrenergic projections and noradrenaline levels in the hippocampus and spinal cord.
Whole cell recordings in Gpt2-Empty LC slices showed reduced somatic size, abnormal action potentials, and altered firing kinetics.Strikingly, we observed that phosphorylated S6 in Gpt2-Empty LC, prior to significant p62 accumulation, increased the ratio of LC3B-II to LC3B-I, as well as neuronal loss.
These data are consistent with possible mechanisms involving defects in protein synthesis and cell growth, which are subsequently associated with abnormal autophagy and neurodegeneration.
Loss of LC neurons compared to few genetic animal models with LC degeneration Gpt2-Null mice are the earliest to develop. Early neuronal loss in LC in human neurometabolic disease models provides important clues about the metabolic vulnerability of LC and may lead to new therapeutic targets.