Link identified between nerve cell proteins and middle-age onset dementia

February 13, 2017, Nagoya University
Fused in sarcoma (FUS) and its binding partner proline- and glutamine-rich (SFPQ) regulates Mapt splicing, resulting balanced ratio of tau isoforms. Loss of interaction between FUS and SFPQ alters Mapt splicing, and subsequently increases 4-repeat tau/ 3-repeat tau ratio. This unbalanced tau isoform ratio leads to a neurodegenerative phenotype similar to FTLD. Credit: Yusuke Fujioka, Shinsuke Ishigaki, and Gen Sobue

Nagoya University-led research identifies role for neuronal protein interaction in preventing frontotemporal lobar degeneration, a dementia that starts in middle age.

Frontotemporal lobar degeneration (FTLD) is a type of dementia characterized by personality changes, language dysfunction, and abnormal behavior. It has an earlier onset than Alzheimer's disease, and is associated with a buildup of the in affected nerve cells (neurons).

Nagoya University-led Japanese research has now revealed that loss of the interaction between two RNA binding proteins changes the expression ratio of different forms of tau , producing the FTLD phenotype in mice, and that this could be rescued by rebalancing the tau ratio. The study was reported in Cell Reports.

The RNA binding protein FUS is linked to both familial and sporadic FTLD/ALS. The researchers investigated other proteins that bind the FUS complex within the nucleus and found another RNA metabolism regulator, SFPQ, to be key to the complex formation.

Both FUS and SFPQ control the process known as by which exons of a gene are joined to other exons or skipped altogether to produce different messenger RNAs and, consequently, different versions (isoforms) of the same protein. FUS/SFPQ-regulated alternative splicing of the Mapt gene at exon 10 produces two different tau isoforms (4R-T and 3R-T) that are usually balanced. However, the team showed that FUS or SFPQ silencing resulted in an excess of 4R-T over 3R-T.

The researchers generated mice lacking expression of FUS or SFPQ in a region of their brain important for memory and spatial navigation; the hippocampus. These mice were observed to have abnormal behaviors that resembled those of FTLD.

"They also had a reduced hippocampal volume, loss of neuronal cells, and less nerve cell growth than control animals," study first author Shinsuke Ishigaki says. "Crucially, the mice showed increased levels of a modified form of tau that is a known hallmark of FTLD and other neurodegenerative diseases."

The team attempted to rescue this disease phenotype in by rebalancing the 4R-T/3R-T ratio. "We achieved this by introducing a short sequence of RNA to block 4R-T expression," corresponding author Gen Sobue explains. "This recovered most of the changes associated with FTLD that had been caused by FUS or SFPQ silencing."

The researchers confirmed that the link between FUS/SFPQ and tau isoform regulation also exists in humans using a model from human stem cell-derived neurons and a mini-gene, implying a role for tau isoform imbalance in FTLD development in humans.

Explore further: Is it Alzheimer's disease or another dementia? Marker may give more accurate diagnosis

More information: Shinsuke Ishigaki et al. Altered Tau Isoform Ratio Caused by Loss of FUS and SFPQ Function Leads to FTLD-like Phenotypes, Cell Reports (2017). DOI: 10.1016/j.celrep.2017.01.013

Related Stories

Is it Alzheimer's disease or another dementia? Marker may give more accurate diagnosis

November 30, 2011
New research finds a marker used to detect plaque in the brain may help doctors make a more accurate diagnosis between two common types of dementia – Alzheimer's disease and frontotemporal lobar degeneration (FTLD). ...

Study reveals new link between Alzheimer's disease and healthy aging

August 15, 2011
Alzheimer's disease and frontotemporal lobar degeneration (FTLD) are two of the most prevalent forms of neurodegenerative disorders. In a study published online today in Genome Research, researchers have analyzed changes ...

Recommended for you

Animal study connects fear behavior, rhythmic breathing, brain smell center

April 20, 2018
"Take a deep breath" is the mantra of every anxiety-reducing advice list ever written. And for good reason. There's increasing physiological evidence connecting breathing patterns with the brain regions that control mood ...

Mechanism behind neuron death in motor neurone disease and frontotemporal dementia discovered

April 20, 2018
Scientists have identified the molecular mechanism that leads to the death of neurons in amyotrophic lateral sclerosis (also known as ALS or motor neurone disease) and a common form of frontotemporal dementia.

When there's an audience, people's performance improves

April 20, 2018
Often, people think performing in front of others will make them mess up, but a new study led by a Johns Hopkins University neuroscientist found the opposite: being watched makes people do better.

Signaling between neuron types found to instigate morphological changes during early neocortex development

April 20, 2018
A team of researchers from several institutions in Japan has found that developing neocortex neurons in mammals undergo a morphological transition from a multipolar shape to a bipolar shape due at least partially to signaling ...

MRI technique detects spinal cord changes in MS patients

April 20, 2018
A Vanderbilt University Medical Center-led research team has shown that magnetic resonance imaging (MRI) can detect changes in resting-state spinal cord function in patients with multiple sclerosis (MS).

Gene variant increases empathy-driven fear in mice

April 20, 2018
Researchers at the Center for Cognition and Sociality, within the Institute for Basic Science (IBS), have just published as study in Neuron reporting a genetic variant that controls and increases empathy-driven fear in mice. ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.