Nav: Home

Unlocking the mystery of tau for treatment of neurodegenerative diseases

September 09, 2020

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.
-end-
The paper, "Aberrant interaction between FUS and SFPQ in neurons in a wide range of FTLD spectrum diseases," was published in the journal BRAIN on August 8, 2020 at DOI: 10.1093/brain/awaa196.

About Nagoya University, Japan

Nagoya University has a history of about 150 years, with its roots in a temporary medical school and hospital established in 1871, and was formally instituted as the last Imperial University of Japan in 1939. Although modest in size compared to the largest universities in Japan, Nagoya University has been pursuing excellence since its founding. Six of the 18 Japanese Nobel Prize-winners since 2000 did all or part of their Nobel Prize-winning work at Nagoya University: four in Physics - Toshihide Maskawa and Makoto Kobayashi in 2008, and Isamu Akasaki and Hiroshi Amano in 2014; and two in Chemistry - Ryoji Noyori in 2001 and Osamu Shimomura in 2008. In mathematics, Shigefumi Mori did his Fields Medal-winning work at the University. A number of other important discoveries have also been made at the University, including the Okazaki DNA Fragments by Reiji and Tsuneko Okazaki in the 1960s; and depletion forces by Sho Asakura and Fumio Oosawa in 1954.

Nagoya University

Related Neurodegenerative Diseases Articles:

First 'pathoconnectome' could point toward new treatments for neurodegenerative diseases
Scientists from the John A. Moran Eye Center at the University of Utah have achieved another first in the field of connectomics, which studies the synaptic connections between neurons.
Unlocking the mystery of tau for treatment of neurodegenerative diseases
A team of researchers from various collaborating universities and hospitals in Japan has uncovered crucial molecular details regarding the activity of the ''tau'' protein, promising to revolutionize the therapy of tau-induced neurodegenerative diseases.
Investigational drug stops toxic proteins tied to neurodegenerative diseases
An investigational drug that targets an instigator of the TDP-43 protein, a well-known hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), may reduce the protein's buildup and neurological decline associated with these disorders, suggests a pre-clinical study from researchers at Penn Medicine and Mayo Clinic.
Inhibition of sphingolipid metabolism and neurodegenerative diseases
Disrupting the production of a class of lipids known as sphingolipids in neurons improved symptoms of neurodegeneration and increased survival in a mouse model.
How understanding the dynamics of yeast prions can shed light on neurodegenerative diseases
How understanding the dynamics of yeast prions can shed light on neurodegenerative diseases
New family of molecules to join altered receptors in neurodegenerative diseases
An article published in the Journal of Medicinal Chemistry shows a new family of molecules with high affinity to join imidazoline receptors, which are altered in the brain of those patients with neurodegenerative diseases such as Alzheimer's, Parkinson's and Huntington's.
Examining diagnoses of stress-related disorders, risk of neurodegenerative diseases
Researchers investigated how stress-related disorders (such as posttraumatic stress disorder, adjustment disorder and stress reactions) were associated with risk for neurodegenerative diseases, including Alzheimer and Parkinson disease and amyotrophic lateral sclerosis (ALS), using data from national health registers in Sweden.
Toxic protein, linked to Alzheimer's and neurodegenerative diseases, exposed in new detail
The protein tau has long been implicated in Alzheimer's and a host of other debilitating brain diseases.
Study uncovers unexpected connection between gliomas, neurodegenerative diseases
New basic science and clinical research identifies TAU, the same protein studied in the development of Alzheimer's, as a biomarker for glioma development.
Neurodegenerative diseases may be caused by transportation failures inside neurons
Protein clumps are routinely found in the brains of patients with neurodegenerative diseases.
More Neurodegenerative Diseases News and Neurodegenerative Diseases Current Events

Trending Science News

Current Coronavirus (COVID-19) News

Top Science Podcasts

We have hand picked the top science podcasts of 2020.
Now Playing: TED Radio Hour

Listen Again: The Power Of Spaces
How do spaces shape the human experience? In what ways do our rooms, homes, and buildings give us meaning and purpose? This hour, TED speakers explore the power of the spaces we make and inhabit. Guests include architect Michael Murphy, musician David Byrne, artist Es Devlin, and architect Siamak Hariri.
Now Playing: Science for the People

#576 Science Communication in Creative Places
When you think of science communication, you might think of TED talks or museum talks or video talks, or... people giving lectures. It's a lot of people talking. But there's more to sci comm than that. This week host Bethany Brookshire talks to three people who have looked at science communication in places you might not expect it. We'll speak with Mauna Dasari, a graduate student at Notre Dame, about making mammals into a March Madness match. We'll talk with Sarah Garner, director of the Pathologists Assistant Program at Tulane University School of Medicine, who takes pathology instruction out of...
Now Playing: Radiolab

What If?
There's plenty of speculation about what Donald Trump might do in the wake of the election. Would he dispute the results if he loses? Would he simply refuse to leave office, or even try to use the military to maintain control? Last summer, Rosa Brooks got together a team of experts and political operatives from both sides of the aisle to ask a slightly different question. Rather than arguing about whether he'd do those things, they dug into what exactly would happen if he did. Part war game part choose your own adventure, Rosa's Transition Integrity Project doesn't give us any predictions, and it isn't a referendum on Trump. Instead, it's a deeply illuminating stress test on our laws, our institutions, and on the commitment to democracy written into the constitution. This episode was reported by Bethel Habte, with help from Tracie Hunte, and produced by Bethel Habte. Jeremy Bloom provided original music. Support Radiolab by becoming a member today at Radiolab.org/donate.     You can read The Transition Integrity Project's report here.