proteomics
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Mapping dementialinked protein interactions
By mapping all the interactions of a dementia-linked protein in the brain called tau, investigators at Weill Cornell Medicine have created a roadmap for identifying potential new treatment targets for Alzheimer’s disease and related dementia.
M
to participate in diverse neuronal functions. To
link dysregulated energy metabolism with
develop an atlas that maps the interactions modified
neurodegeneration, but the mechanism remains
by disease-causing mutations and neuronal activity,
elusive. We found disease-causing mutations reduce
Dr Gan and colleagues grew human neurons from
tau–mitochondrial protein interaction and impair
utations in the gene that
induced pluripotent stem cells that carry normal
mitochondrial function.”
encodes the tau protein are known to
tau gene or tau gene with mutations that cause
When they analysed patient data from the
result in neurodegenerative conditions like
frontotemporal dementia. They used a technique
Accelerating Medicines Partnership Program
frontotemporal dementia, while in Alzheimer’s
called quantitative affinity purification–mass
for Alzheimer’s Disease (AMP AD), Dr Gan and
disease the protein accumulates and becomes
spectrometry (AP–MS), which enables the study of
her team found that patients with Alzheimer’s
toxic. But the exact role of the tau protein in
protein interactions, to compare how normal and
disease had lower levels of tau-interacting proteins,
these diseases has remained a mystery.
disease-causing mutants of tau behave. To capture
including mitochondria proteins. Patients with the
To help solve this mystery, Dr Li Gan and her
how neuronal activity alters the tau interactome, they
most severe disease had the lowest levels of tau-
colleagues created a comprehensive atlas, called a
used a cutting-edge technology called engineered
interacting proteins, suggesting that the discovery
Tau interactome, that maps all the tau protein’s
ascorbic acid peroxidase (APEX) to label proteins
they made in neurons is relevant to human patients.
interactions with other proteins in human neurons
in close proximity to tau within milliseconds.
The team will next investigate if strategies
grown in the laboratory. Dr Gan noted, “Tau is at
“The combination of two highly quantitative
elevating mitochondria–tau interactions could
the centre of neurodegeneration, and understanding
proteomic technologies has allowed us to establish
enhance energy metabolism to counteract the
how it causes toxicity and cognitive decline has the
Tau interactions with unprecedented spatial and
effects of disease-causing tau protein. They are
potential to lead to new therapies to treat dementia.”
time resolution in human neurons,” Dr Gan said.
also studying which cellular processes allow toxic
The team’s results, published in the journal Cell,
Unexpectedly, the team discovered that tau
versions of tau to spread throughout the brain via
reveal that mutations that diminish the interactions
interacts with proteins that are released into the
the synapses to see if they can be stopped. Dr Gan
between tau and mitochondrial proteins may hamper
synapses that send signals to neighbouring neurons.
also thinks her team’s research may help scientists
energy production in the brain, the most energy-
This may allow disease-causing versions of tau to
develop novel biomarkers to detect the early signs
intensive organ in the body. Additionally, they found
spread from one region of the brain to another
of mitochondrial dysfunction, allowing clinicians
that tau interacts with proteins in the synaptic sites
and help explain the phenomenon that neurons
to intervene earlier in the course disease.
that send electric signals to other neurons, which
that fire together often die together, Dr Gan said.
“The Tau interactome atlas provides an
may provide clues on how toxic tau protein spreads
Another surprise finding is that tau proteins
exciting roadmap for scientific community to
in brains with tau pathology.
have strong interactions with many proteins in
explore new therapeutic targets and biomarkers
In normal and diseased neurons, tau protein
the energy-producing mitochondria of neurons.
for Alzheimer disease and related dementia,”
forms physical interactions with specific proteins
According to Dr Gan, “More and more studies
Dr Gan said.
26 | LAB+LIFE SCIENTIST - Feb/Mar 2022
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