The locus coeruleus is among the first brain regions to degenerate in Alzheimer’s and Parkinson’s disease, physicians and scientists have known. But why this area is so vulnerable is less understood.
While continuing their exploration of a
rare neurogenetic disorder, a team of Brown University researchers discovered
explanations that shed light on this important question.
In the journal Neurobiology of Disease,
the researchers report a novel mechanism of degeneration in the locus coeruleus neurons
caused by the loss of a mitochondrial enzyme, GPT2, which is implicated in the
neurological disorder on which the researchers are focused.
“These findings represent a new
direction of research on this really important part of the brain,” said study
author Dr. Eric Morrow, a professor of biology, neuroscience, psychiatry and
human behavior at the Warren Alpert Medical School, and director of Brown
University’s Center for Translational Neuroscience.
Located in the brainstem, the locus
coeruleus is a critical area that houses a major source of neurons, providing
the neurotransmitter norepinephrine via projections throughout the brain.
Norepinephrine is a common drug target for many disease treatments, Morrow
said.
The locus coeruleus is involved in a
variety of cognitive processes such as attention, learning, mood, wakefulness
and sleep. The death of the neurons in this part of the brain is also
implicated in cognitive diseases such as Alzheimer’s and Parkinson’s. In recent
years, the locus coeruleus has become an area of widespread and intense
research interest, Morrow said. Yet his team did not originally endeavor to
study this part of the brain in its experiments.
“That’s one of the things that makes this
discovery so exciting,” Morrow said. “This was a completely serendipitous
finding that, frankly, could have been missed. This is an example of how
research focusing on genetic information can teach us previously unforeseen
lessons about the brain.”
The team, which included Brown
neuroscience graduate student Ozan Baytas, had been investigating how a
specific genetic mutation is implicated in a rare, neurogenetic disorder called
GPT2 Deficiency — a genetic syndrome that the Morrow lab first reported in 2016. The gene of interest is called GPT2 (Glutamate Pyruvate Transaminase
2), and it generates an enzyme that is vital to metabolic pathways in
mitochondria, the energy centers of cells.
After introducing the mutation into the
metabolic gene in lab mice to study GPT2 Deficiency, the researchers discovered
that this loss of mitochondrial enzyme caused the locus coeruleus to degenerate
relatively early and selectively in the lifespan of the mouse.
The GPT2 enzyme regulates neuronal
growth through replenishment of tricarboxylic acid cycle intermediates and the
modulation of amino acid metabolism. In mice that do not have the GPT2 enzyme,
the researchers observed an early loss of neurons in the locus coeruleus, as
well as other signs of degeneration, such as deficiency in protein synthesis
and stunted cell growth.
A specific part of the work involved the
electrophysiology of neurons. Those experiments were performed in the
laboratory of co-author Julie Kauer, then at Brown and now professor of
psychiatry and behavioral sciences at Stanford University.
“Our results suggest that altered
metabolism may be the initial driving force for neurodegeneration in locus
coeruleus,” said lead study author Baytas. “Pinpointing the exact causes of
this degeneration may inform us of the mechanisms of disease in the locus
coeruleus that we can correct, or better still prevent, in order to stop
dementia and related behavioral conditions. The findings in our mouse model of
a neurometabolic disease open up a new outlook on neurodegeneration of locus
coeruleus and encourage further research on metabolic susceptibility of these
neurons.”
Because of the focus on the locus
coeruleus in the development of drug treatments, Morrow said this finding about
the early impairment of this brain region will have interest to a broad range
of people in the neuroscience and neuropsychiatric community. The hope, he
added, is that these studies will eventually culminate in therapeutic targets for
Alzheimer’s disease and other neurodegenerative diseases.
Source: https://www.brown.edu/news/2022-09-01/locus-coeruleus
Images from the paper show indicators of
neurodegeneration in the locus coeruleus part of the brain. This is reflected
by purple neurons surrounded by activated green glial cells in the animal model
of GPT2 Deficiency (“GPT2-null”). Credit: Brown University
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