Unlocking the mystery of tau for treatment of neurodegenerative diseases


Date:
September 9, 2020
Source:
Nagoya University
Summary:
A team of researchers has uncovered crucial molecular details
regarding the activity of the 'tau' protein, promising to
revolutionize the therapy of tau-induced neurodegenerative diseases.



FULL STORY ========================================================================== Frontotemporal lobar degeneration (FTLD) is a type of dementia that
appears earlier in life than Alzheimer's disease (AD). Both FTLD and AD,
along with several other neurodegenerative diseases, are marked by the appearance and clustering of the protein "tau" in nerve cells. However,
there is much left to be explored about this mechanism.


==========================================================================
Now, a team of researchers from various collaborating universities and hospitals in Japan has uncovered crucial molecular details regarding
tau's activity, promising to revolutionize the therapy of tau-induced neurodegenerative diseases. Their findings were recently published in
the journal BRAIN.

Tau-induced neurodegenerative diseases include not only FTLD and AD, but
also an array of conditions like amyotrophic lateral sclerosis (ALS), progressive supranuclear palsy (PSP), and corticobasal degeneration
(CBD). Many people from various age groups are affected by the tau-induced diseases, but the effective therapeutic strategy against tau aggregation
is yet to be available. One reason behind this gap is that, despite a
lot of effort and resource invested, the exact mechanism of the action
of tau inside the cell is still unclear. Knowing this will help us pin
down an appropriate treatment strategy.

The aforementioned research team, led by Dr Shinsuke Ishigaki of Nagoya University Graduate School of Medicine, has now discovered new layers of complexities hidden in the cellular activities of tau. The researchers
report a novel role of tau that is specific for FTLD spectrum diseases,
and as per their findings published in BRAIN, these finer mechanisms specifically contribute to the development of conditions such as FTLD,
ALS, PSP, and CBD, but not in AD and Pick's diseases.

However, while this research puts tau in the spotlight, it all started
with another related protein. Dr Ishigaki explains the reasons for
arriving at their study question: "Earlier, while studying FTLD mouse
models, we found two interacting proteins, fused in sarcoma (FUS) and
splicing factor, proline- and glutamine-rich (SFPQ), were important
for the generation of functional tau. The interaction of FUS and
SFPQ inside the nucleus is disrupted due to mutations in FUS results
in neurodegeneration by the accumulation of a dysfunctional variant
'4-repeat tau', causing FTLD in mouse." So how did the researchers
link their findings of mouse model to the tau- induced pathogenesis in
humans? They studied the interaction of SFPQ and FUS in brain autopsy
samples of 142 deceased individuals with various neurodegenerative
diseases like FUS-related ALS/FTLD, TDP-43-related ALS/FTLD, PSP, AD,
or Pick's disease, with the latter disease used as a control to compare
the results.

Using their findings, the researchers have proposed a unique model of "imbalanced accumulation of tau" in cells. As per this new model,
FUS and SFPQ regulate the processing of MAPT, the gene that "codes"
for tau, specifically by removing a genetic region called exon 10. In
normal conditions, the balance in the ratio of variants "4-repeat tau"
and "3-repeat tau" is maintained by MAPT.

In disease conditions, the processing of MAPT is hampered, leading to
an unchecked increase in the amount of 4-repeat tau. Interestingly,
an increased level of 4-repeat tau causes FTLD spectrum diseases, but
not AD or Pick's disease, in humans.

"Now that we know how tau specifically causes FTLD spectrum diseases, we
can design a treatment strategy for these diseases that could 'target'
the factors involved in the process, like '4-repeat tau' or FUS/SFPQ
proteins," concludes Dr Ishigaki, talking about the significance of
their discovery.


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


========================================================================== Journal Reference:
1. Shinsuke Ishigaki, Yuichi Riku, Yusuke Fujioka, Kuniyuki Endo,
Nobuyuki
Iwade, Kaori Kawai, Minaka Ishibashi, Satoshi Yokoi, Masahisa
Katsuno, Hirohisa Watanabe, Keiko Mori, Akio Akagi, Osamu Yokota,
Seishi Terada, Ito Kawakami, Naoki Suzuki, Hitoshi Warita, Masashi
Aoki, Mari Yoshida, Gen Sobue. Aberrant interaction between FUS and
SFPQ in neurons in a wide range of FTLD spectrum diseases. Brain,
2020; 143 (8): 2398 DOI: 10.1093/ brain/awaa196 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/09/200909085957.htm

--- up 2 weeks, 2 days, 6 hours, 50 minutes
* Origin: -=> Castle Rock BBS <=- Now Husky HPT Powered! (1337:3/111)