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Unexpected protein could play role in brain disorder
Scientists have known for years that amyloid fibrils – fibrous, rope-like structures formed by closely linked protein molecules – are present in the brains of patients with Alzheimer’s and Parkinson’s diseases and likely play a role in the progression of these disorders.
Now, UCLA biochemists have discovered such fibrils in the brains of people with a form of frontotemporal lobar degeneration, or FTLD, the most common neurodegenerative disorder after Alzheimer’s and Parkinson’s.
But surprisingly, the type of protein they expected to find in these potentially harmful fibrils wasn’t there at all; instead, a little-known protein called TMEM106B was identified as the culprit.
The findings, published in the journal Nature, are likely to lead to a new focus on TMEM106B in FTLD and similar brain diseases, the researchers said.
FTLD, which involves damage to the brain’s frontal and temporal lobes, strikes people earlier in life than Alzheimer’s and Parkinson’s, causing dementia in 80 out of 100,000 people between the ages of 45 and 64.
Symptoms can include acute changes in behaviour and a decline in language skills.
The form of the disease studied by the researchers is characterised molecularly by dense, spherical aggregates in brain cells, which are made up of the protein TDP-43.
The UCLA team presumed that if there were amyloid fibrils in the brains of people with FTLD, these fibrils would be composed of TDP-43.
The study’s lead authors, UCLA molecular biology graduate student Yi Xiao (Sean) Jiang and UCLA postdoctoral fellow Qin Cao, both working in laboratory of UCLA professor David Eisenberg, were indeed able to extract amyloid fibrils from frozen brain tissues provided by the Mayo Clinic from four deceased patients who had been diagnosed with FTLD-TDP.
However, using a technique called cryogenic electron microscopy, or cryo-EM – which allowed them to image large biomolecules in extraordinary detail – they, along with UCLA bioinformatics researcher Michael Sawaya, determined that the fibrils were composed solely of TMEM106B, or transmembrane protein 106B.
Not much is known about TMEM106B, although genetic scientists found evidence a decade ago that a mutation of the protein is a risk factor for FTLD, said senior author Eisenberg, the Paul Boyer Professor of Molecular Biology at UCLA and a Howard Hughes Medical Institute investigator.
A golf course
Pathological deposits of amyloid proteins are associated with more than 50 degenerative and potentially fatal diseases, according to Eisenberg, who has studied amyloid fibrils for years.
In a 2005 Nature paper, Eisenberg and an international team of chemists and molecular biologists reported that these fibrils are made up of proteins that interlock like the teeth of a zip — an observation that has been supported by recent studies. TMEM106B, he said, forms multiple molecular zips.
The team’s structural analysis of TMEM106B fibrils shows that they share features with the pathogenic fibrils seen in Alzheimer’s and Parkinson’s but are more complex, Eisenberg noted.
Like those other fibrils, they are made of stacks of thousands of layers, each layer formed by single protein molecules with straight segments and bent corners, folding into a complex shape (see image above).
In TMEM106B, the folded protein chain has 18 straight segments, which the researchers liken to the 18 fairways of a golf course – and like a golf course, the first and 18th fairways are near each other. “So we say TMEM106B has a golf course-like fold,” Eisenberg said.
Whether the TMEM106B amyloid fibrils contribute to causing FTLD-TDP remains to be seen.
It is also unclear what, if any, role may be played by the TDP-43 proteins, whose normal function is to shepherd RNA molecules carrying DNA blueprints for proteins from the nucleus of brain cells to the cytoplasm.
“TMEM106B may be found to be a cause of FTLD. In that case, our knowledge of the structure will aid in the design of therapeutics,” Eisenberg said.
“Further research may also discover a connection between the actions of TMEM106B and TDP-43. It’s too early to tell.
“But at the least, the present paper will alert the community of researchers studying neurodegeneration that a new protein may potentially play a role,” he said.
UCLA co-authors of the paper are Romany Abskharon, Peng Ge, Janine Fu, Rachel Ogorzalek and Joseph Loo.
Michael DeTure and Dennis Dickson of the Mayo Clinic in Jacksonville, Florida, provided patient tissues and contributed neuropathological analyses.
Lead author Cao now heads his own lab at China’s Shanghai Jiao Tong University.
Funding sources included the National Institute on Aging, part of the National Institutes of Health, and the Howard Hughes Medical Institute.
The project aims to identify people at risk of dementia before symptoms appear.
More than 7 million people are living with dementia in the EU. This number is projected to double, reaching 14 million by 2050.
There is currently no cure for Alzheimer’s disease. Although the search for potential treatments is showing promise, it is anticipated that these medications will be most effective in the early stages of the disease.
The recently launched AI screening platform, PREDICTOM aims to identify individuals at risk of developing dementia, even before symptoms manifest.
The cognitive and biomarker screening platform has this week announced it will be backed by €21 million in funding, with €8 million from the EU, €9 million from industry and €4 million from UKRI.
A consortium of 30 partners from academia, business, civil society and hospitals is steering the project. The Consortium includes partners from 15 countries across Europe, Asia and America and is led by Stavanger University Hospital.
Dag Aarsland, Professor of Old Age Psychiatry at King’s College London and research lead at Stavanger University Hospital, is the leading the project.
“Detecting early signs of dementia is key to slowing its progression. Unfortunately, a majority of those at risk are not identified in time. Our platform seeks to change this by enabling early discovery, allowing timely intervention and preventative treatment,” Aarsland said.
A crucial aspect of PREDICTOM is that much of the screening can be performed by the patients themselves in the comfort of their homes.
By initiating the process at home, the project aims to reduce strain on healthcare services and associated costs. Biomarkers, including saliva, stool, digital markers and blood via prick-tests, will be collected at participants’ homes or GP offices, streamlining a process traditionally carried out in hospitals or specialised clinics.
More than 4000 participants will partake in PREDICTOM’s trial project. The samples will be based on a pool of people from previous initiatives like PROTECT UK, PROTECT Norway and Radar-AD, as well as people from the catchment area of other participating centres in Germany, France, Switzerland, Belgium and Spain.
“If our project succeeds, there will be significant savings in both cost and time,” Aarsland said
After the home collection, samples will be sent to PREDICTOM, where their platform will process the participant data, integrating blood, cerebrospinal fluid, imaging, electrophysiological and digital biomarkers.
AI algorithms will generate risk assessments, early diagnoses and prognoses, laying the foundation for early intervention and treatment.
This project is part of the Innovative Health Initiative (IHI), a public-private partnership (PPP) between the European Union and the European life science industries.
“We are very pleased to have such a robust team with top notch expertise spanning diverse fields, including IT, AI, medicine, ageing research and professionals from both small and large businesses,” Aarsland added.
The project runs from 1st November 2023 to 31st October 2027.
The partnership will bring non-pharmacological interventions for dementia and alternatives to high-cost drugs to patients across Washington State.
A new partnership between brain health company, Together Senior Health and accountable care organisation, Rainier Health Network,
The partnership will introduce Together’s suite of dementia-specific programs, including in-home virtual interventions, to patients across Rainier Health Network in Washington state where the organisation oversees the healthcare of over 60,000 Medicare patients.
Alzheimer’s and related dementias affect more than 6.7 million Americans with 14 million projected cases by 2060. The associated healthcare costs for individuals with dementia are among the highest of any condition. Payers and providers face significant challenges in managing this expanding population.
According to a recent survey conducted by Sage Growth Partners, 77 per cent of health plans and value-based care organizations agree the need to address the growing cost of ADRD is urgent or very urgent; however, only 4 per cent have a fully-developed solution in place to support this population.
Approximately half of those surveyed also indicated a concern with the costs of Leqembi and other high-cost pharmaceuticals.
Together’s Moving Together programme offers a non-pharmacological intervention for dementia and a safe alternative to high-cost drugs that are not clinically appropriate for many dementia patients and have potential side effects.
The programme allows payers and risk-bearing healthcare organisations to more effectively manage patients. Together Senior Health says the programme results in improved engagement, reduced costs and improved health outcomes.
Recently, the company has been gaining industry traction. In addition to its partnership with Rainer Health Network, the firm is affiliated with the likes of VNS Health, VillageMD and the Alzheimer’s Association.
“Supporting our members with Alzheimer’s disease and related dementias is critical,” said Dr Francis Mercado chief medical officer and board chair at Rainier Health Network. “It’s a vulnerable population and Together Senior Health’s Moving Together™ solution is a proven, natural way to improve their lives and control costs.”
Together’s Moving Together™ programme is based on over ten years of clinical research in neuroscience with the University of California, San Francisco (UCSF) and the National Institutes of Health (NIH).
Results from Together’s randomised control trial show statistically significant improvements in quality of life for individuals with cognitive decline and in caregiver ability to manage stress. The data also shows a reduction in falls and proven annual cost savings of up to $4,300 per participant per year.
Caregivers in the programme have also benefited, reporting enhanced caregiving skills.
Together is in the process of commercialising RADAR, its proprietary dementia identification and stratification algorithm. The algorithm helps payors and risk-bearing healthcare organisations identify people at highest risk for Alzheimer’s disease, dementia and cognitive decline using claims data, electronic health record information and other relevant data.
“We are proud of the positive impact Together is making on the lives of those affected by dementia and are excited to partner with one of the nation’s premier ACOs to extend dementia-specific programs to its patients,” said Alissa Meade, CEO of Together Senior Health.
“Rainier Health Network, Virginia Mason Franciscan Health and Together share a deep commitment to providing holistic dementia solutions that enrich the lives of participants while empowering forward-thinking, risk-bearing organizations to engage and manage this rapidly growing patient population effectively.”
The study used genomic data from 58,000 Icelanders and discovered the presence of a life-shortening genotype across 4 per cent of the population.
Scientists at deCODE Genetics, a subsidiary of Amgen, have published a study on actionable genotypes detected in the Icelandic population and their association with lifespan.
The researchers determined that 1 in 25 individuals carried an actionable genotype and have, on average, a shortened lifespan.
“The identification and disclosure of actionable genotypes to participants can guide clinical decision-making, which may result in improved patient outcomes,” said Kari Stefansson, author of the paper and CEO of deCODE Genetics. “This knowledge therefore has significant potential to mitigate disease burden for individuals and society as a whole.”
The study, published today in the New England Journal of Medicine, focuses on genotypes that increase the risk of a disease for which preventive or therapeutic measures have been established. These genotypes are termed actionable genotypes.
The scientists used a population-based data set, consisting of 58,000 whole-genome sequenced Icelanders, to assess the fraction of individuals carrying actionable genotypes.
Using a list of 73 actionable genes from the guidelines from the American College of Medical Genetics and Genomics (ACMG), the scientists found that 4 per cent of Icelanders carry an actionable genotype in one or more of these genes. The diseases caused by these genotypes include cardiovascular, cancer and metabolic diseases.
The study assessed the relationship between actionable genotypes and the lifespan of their carriers. The largest effect was observed among carriers of cancer-predisposing genotypes, which had three years shorter median survival than non-carriers.
A pathogenic variant in BRCA2, predisposing to breast, ovarian and pancreatic cancer, shortened lifespan by seven years and a variant in LDLR, which causes high levels of cholesterol and cardiovascular disease, shortened lifespan by six years.
“Our results suggest that the actionable genotypes identified in our study, which are all predicted to cause serious disease, may have a drastic effect on lifespan,” said Patrick Sulem author of the paper and scientist at deCODE Genetics.
The results showed that carriers of particular actionable genotypes were more likely to have died from the disease caused by these genotypes. Individuals with a pathogenic variant in BRCA2, have a seven-fold risk of dying from breast, ovarian or pancreatic cancer.
They are also 3.5 times more likely to develop prostate cancer and seven times more likely to die from prostate cancer than those who do not carry the variant.
The results of this study are among the factors that have motivated the government of Iceland to announce a nationwide effort in precision medicine.
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