Mapping dementia-linked protein interactions yields potential new
treatment targets

Date:
January 20, 2022
Source:
Weill Cornell Medicine
Summary:
By mapping all the protein interactions of a dementia-linked protein
in the brain called Tau, a team of investigators has created a road
map for identifying potential new treatment targets for Alzheimer's
disease and related dementia.



FULL STORY ==========================================================================
By mapping all the protein interactions of a dementia-linked protein
in the brain called Tau, a team of Weill Cornell Medicine investigators
has created a road map for identifying potential new treatment targets
for Alzheimer's disease and related dementia.


==========================================================================
Tau protein has long been implicated in neurodegenerative
diseases. Mutations in the gene that encodes the Tau protein result
in neurodegenerative conditions like frontotemporal dementia, while in Alzheimer's disease the protein accumulates and becomes toxic. But the
exact role of the Tau protein in these diseases have remained a mystery.

To help solve this mystery, senior author Dr. Li Gan, director of the
Helen and Robert Appel Alzheimer's Disease Research Institute, and her colleagues created a comprehensive atlas, called Tau interactome, that
maps all the Tau protein's interactions with other proteins in human
neurons grown in the laboratory. The results, published Jan. 20 in the
journal Cell, reveal that mutations that diminish the interactions between
Tau and mitochondrial proteins may hamper energy production in the brain,
the most energy-intensive organ in the body.

Additionally, they found that Tau interacts with proteins in the synaptic
sites that send electric signals to other neurons, which may provide
clues on how toxic Tau protein spreads in brains with Tau pathology.

"Tau is at the center of neurodegeneration, and understanding how it
causes toxicity and cognitive decline has the potential to lead to
new therapies to treat dementia," said Dr. Gan, who is also the Burton
P. and Judith B. Resnick Distinguished Professor in Neurodegenerative
Diseases in the Feil Family Brain and Mind Research Institute at Weill
Cornell Medicine.

In normal and diseased neurons, Tau protein forms physical interactions
with specific proteins to participate in diverse neuronal functions. To
develop an atlas that maps the interactions modified by disease-causing mutations and neuronal activity, Dr. Gan and her colleagues grew human
neurons from induced pluripotent stem cells that carry normal Tau gene
or Tau gene with mutations that cause frontotemporal dementia. They used
a technique called quantitative affinity purification mass spectrometry (AP-MS), which enables the study of protein interactions, to compare
how normal and disease-causing mutants of Tau behave. To capture how
neuronal activity alters the Tau interactome, they used a cutting-edge technology called engineered ascorbic acid peroxidase (APEX) to label
proteins in close proximity to Tau within milliseconds.

"The combination of two highly quantitative proteomic technologies has
allowed us to establish Tau interactions with unprecedented spatial and
time resolution in human neurons," said Dr. Gan, who is a co-founder
with equity and consultant for Aeton Therapeutics, Inc.

Unexpectedly, the team discovered that Tau interacts with proteins
that are released into the synapses that send signals to neighboring
neurons. This may allow disease-causing versions of Tau to spread from
one region of the brain to another and help explain the phenomena that
neurons fire together often die together, Dr. Gan said.

Another surprise finding is that they found Tau proteins have strong interactions with many proteins in the energy-producing mitochondria
of neurons.

"More and more studies link dysregulated energy metabolism with neurodegeneration, but the mechanism remains elusive," she said. "We found disease-causing mutations reduce Tau-mitochondrial protein interaction
and impair mitochondrial function." When they analyzed patient data from
the Accelerating Medicines Partnership - - Alzheimer's Disease (AMP-AD),
Dr. Gan and her team found that patients with Alzheimer's disease
had lower levels of Tau-interacting proteins, including mitochondria
proteins. Patients with the most severe disease had the lowest levels
of Tau-interacting proteins, suggesting that the discovery they made in
neurons is relevant to human patients.

Dr. Gan and her team will next investigate if strategies elevating
the mitochondria Tau interactions could enhance energy metabolism
to counteract the effects of disease-causing Tau protein. They are
also studying which cellular processes allow toxic versions of Tau
to spread throughout the brain via the synapses to see if they can be
stopped. Dr. Gan also thinks her team's research may help scientists
develop novel biomarkers to detect the early signs of mitochondrial dysfunction, allowing clinicians to intervene earlier in the course
disease.

"The Tau interactome atlas provides an exciting roadmap for scientific community to explore new therapeutic targets and biomarkers for Alzheimer disease and related dementia," Dr. Gan said.

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========================================================================== Journal Reference:
1. Tara E. Tracy, Jesus Madero-Pe'rez, Danielle L. Swaney, Timothy
S. Chang,
Michelle Moritz, Csaba Konrad, Michael E. Ward, Erica
Stevenson, Ruth Hu"ttenhain, Grant Kauwe, Maria Mercedes, Lauren
Sweetland-Martin, Xu Chen, Sue-Ann Mok, Man Ying Wong, Maria
Telpoukhovskaia, Sang-Won Min, Chao Wang, Peter Dongmin Sohn,
Jordie Martin, Yungui Zhou, Wenjie Luo, John Q. Trojanowski,
Virginia M.Y. Lee, Shiaoching Gong, Giovanni Manfredi, Giovanni
Coppola, Nevan J. Krogan, Daniel H. Geschwind, Li Gan.

Tau interactome maps synaptic and mitochondrial processes associated
with neurodegeneration. Cell, 2022; DOI: 10.1016/j.cell.2021.12.041 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/01/220120135120.htm

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