Tau and PQBP1: Protein interaction induces inflammation in the brain


Date:
December 8, 2021
Source:
Tokyo Medical and Dental University
Summary:
Researchers have clarified the relationship between the
intracellular receptor PQBP1 and the structural protein Tau, which
is dysregulated in neurodegenerative diseases such as Alzheimer's
disease. Tau was found to interact with PQBP1 in immune cells of
the brain, which led to activation of the inflammatory cGAS-STING
pathway. PQBP1 may represent a potential target for the development
of therapeutics to treat Tau-mediated neurodegenerative diseases.



FULL STORY ==========================================================================
Just as a home security system can alert a homeowner to the presence of
an intruder, a protein called polyglutamine binding protein-1 (PQBP1)
found in brain cells can alert the body to the presence of "intruding"
viruses like human immunodeficiency virus (HIV). Now, researchers in
Japan have shed new light on the role of PQBP1 in the detection of dysfunctional proteins associated with neurodegenerative disorders.


==========================================================================
In a new study published in Nature Communications, researchers from
Tokyo Medical and Dental University (TMDU) have revealed the role of intracellular receptor PQBP1 in response to Tau, a protein found primarily
in neurons that plays a key role in the progression of neurodegenerative disorders like Alzheimer's disease.

PQBP1 has been previously shown to sense and bind HIV DNA and trigger an
immune pathway known as the cGAS-STING pathway to initiate an inflammatory response.

While PQBP1 has also been shown to interact with dysfunctional proteins
such as those implicated in the neurodegenerative disorder Huntington's disease, the specific role of PQBP1 in neurodegenerative inflammatory
responses was unclear.

To better understand this relationship, researchers from TMDU set out
to clarify the nature of the interaction between PQBP1 and Tau.

"By characterizing the relationship between PQBP1 and Tau, we were able
to clarify a mechanism of inflammation in the brain that functions in
both viral infection and neurodegenerative disease," says senior author
of the study, Hitoshi Okazawa.

The researchers performed in vitro analyses using microglia, which are
PQBP1- expressing immune cells found in the brain, to demonstrate that Tau interacts with PQBP1 and that this interaction drives an immune response
via activation of the cGAS-STING pathway. Their study revealed that
the PQBP1-cGAS-STING pathway functions in parallel with TREM2-mediated
pathway, whose mutation is known to associate with Alzheimer's disease genetically.

They went on to use a mouse model in which PQBP1 was conditionally
inactivated in microglia to show that expression of PQBP1 is necessary
for a Tau-induced inflammatory response in vivo.

"We were pleased to find that inactivating PQBP1 in microglia in the
mouse model reduced brain inflammation in response to the injection of
Tau into the brain," says Okazawa.

The team further found that mutations in the PQBP1-binding regions of Tau reduced the inflammation in the brain in response to Tau injection. These findings indicate that PQBP1 may represent a potential target for
the development of therapeutics for the treatment of Tau-mediated neurodegenerative diseases.

========================================================================== Story Source: Materials provided by
Tokyo_Medical_and_Dental_University. Note: Content may be edited for
style and length.


========================================================================== Journal Reference:
1. Meihua Jin, Hiroki Shiwaku, Hikari Tanaka, Takayuki Obita, Sakurako
Ohuchi, Yuki Yoshioka, Xiaocen Jin, Kanoh Kondo, Kyota Fujita,
Hidenori Homma, Kazuyuki Nakajima, Mineyuki Mizuguchi, Hitoshi
Okazawa. Tau activates microglia via the PQBP1-cGAS-STING pathway
to promote brain inflammation. Nature Communications, 2021; 12
(1) DOI: 10.1038/s41467- 021-26851-2 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/12/211208123346.htm

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