PRESS-NEWS.org - Press Release Distribution
PRESS RELEASES DISTRIBUTION

Closing in on Parkinson’s Disease proteins in extracellular vesicles in the blood

Precision diagnostics for diseases that affect the brain and other organs brought closer by new ability to exclusively access contents of organ-derived extracellular vesicles in blood

Closing in on Parkinson’s Disease proteins in extracellular vesicles in the blood
2024-11-01
(Press-News.org)

Closing in on Parkinson’s Disease proteins in extracellular vesicles in the blood

Precision diagnostics for diseases that affect the brain and other organs brought closer by new ability to exclusively access contents of organ-derived extracellular vesicles in blood

By Benjamin Boettner

(BOSTON) — Brain disorders like Parkinson’s (PD) or Alzheimer’s Disease (AD) start to develop in patients much earlier than when their first clinical symptoms appear. Treating patients at these early stages could slow or even stop their disease, but there is currently no way to diagnose brain disorders at those pre-symptomatic stages. Thus far, the specific brain lesions caused by PD, for example, can only be detected by analyzing brain biopsies, which can only be obtained posthumously. 

 

To overcome this critical bottleneck, researchers have been pursuing the new concept of “liquid biopsies,” which involves the easy extraction of blood or other body fluids using non-invasive procedures, and analyzing them for molecules originating from brain and other solid tissues. A particularly promising target in body fluids are “extracellular vesicles” (EVs), tiny membrane-bound sacs released by brain and other cells into their surrounding fluids. These sacs contain a variety of molecules that can be unique to the cells types that produce them, such as the brain, and thus could also carry protected biomarkers for the early onset of Parkinson’s and other brain diseases. 

However, despite recent progress, EV experts haven’t been able to tackle the problem of whether particular biomarker molecules that they measured in isolated EVs are strictly contained inside EVs or non-specifically bound to their surface. This challenge has actually prevented them from being able to make unambiguous conclusions about cargo molecules in EVs from all types of tissues.

Now, a collaborative team led by David Walt, Ph.D. at the Wyss Institute at Harvard University and Brigham and Women’s Hospital (BWH) in Boston has solved this problem by adding a crucial step to an already validated ultra-sensitive protocol. By enzymatically digesting all surface-bound proteins from a purified EV population, they were able to specifically home in on cargo protected inside of EVs while eliminating unspecific “contaminations.” Using their enhanced protocol to measure the PD biomarker ⍺-synuclein in blood, for the first time they were able to accurately determine the small fraction of any protein contained within EVs vs how much of it is present free in total blood plasma. 

Importantly, they integrated this advance with a newly developed ultra-sensitive detection assay for a form of ⍺-synuclein that becomes increasingly phosphorylated during the progression of PD and the related condition Lewy Body Dementia. Analyzing a cohort of patient samples, they could detect an enrichment of the pathological ⍺-synuclein protein inside EVs relative to total plasma. The findings are published in PNAS.

“Research on EVs in our and other groups over the last few decades has steadily advanced our understanding of their complex biology and molecular composition. Yet, the isolation of pure tissue-specific EVs from body fluids like blood or the cerebrospinal fluid surrounding the central nervous system, including the brain, and validating and quantifying their true contents with precise measurements still present formidable technical challenges,” said Wyss Core Faculty member Walt. “Our recent work is providing a solution to help fill this technological gap, and gets us closer to being able to obtain EVs free from contamination in order to use them as rich sources for clinical biomarkers, as we show with the example of phosphorylated ⍺-synuclein.” Walt, who is the faculty lead of the Wyss Institute’s Diagnostic Accelerator, is also the Hansjörg Wyss Professor of Biologically Inspired Engineering at Harvard Medical School (HMS), Professor of Pathology at Brigham and Women’s Hospital, and a Howard Hughes Medical Institute Professor.

From blood to EVs to biomarkers to diagnosis

Especially motivated by the diagnostic promise of EVs for the early diagnosis of PD, AD, and other brain disorders, the Walt group has been systematically filling vital pieces into this technical jigsaw puzzle. With philanthropic support from Good Ventures, the Chan Zuckerberg Initiative, and more recently the Michael J. Fox Foundation, they previously developed a technical framework for quantifying EVs and used this quantification to compare EV isolation methods from body fluids. Their methodology combines a separation technique known as size exclusion chromatography (SEC) to recover most EVs from biofluids with ultra-sensitive “Simoa assays” that allowed them to count single protein molecules associated with EVs that they captured and visualized with specific antibodies. By now, the team has engineered Simoa assays for a variety of EV-specific biomarkers and, importantly, excluded a widely used candidate surface protein, L1CAM, as a target to isolate brain-specific EVs, which provided the field with an important course correction.

“To answer the conceptually simple but technically challenging question of what percentage of a given protein (such as ⍺-synuclein) present in plasma is inside of EVs relative to outside, we used SEC isolation methods that we previously developed to isolate most EVs from plasma together with an optimized ‘proteinase protection assay’ where we use an enzyme to gently but efficiently chew all proteins off the surface of isolated EVs, while leaving the membrane-enclosed EV interior intact.” said co-first author Dima Ter-Ovanesyan, Ph.D., who is a Senior Scientist at the Wyss Institute and spearheads the EV project with co-first author and Postdoctoral Fellow Tal Gilboa, Ph.D.

Also, to measure ⍺-synuclein at very low levels, Gilboa, together with Postdoctoral Fellow Gina Wang, Ph.D. and Wyss Research Assistant Sara Whiteman in the Walt lab, developed a Simoa assay for ⍺-synuclein that is much more sensitive that any previously reported assay. Using this assay in their protocol, the team was able to determine that most of the ⍺-synuclein in EVs isolated using their SEC protocol was protected and that this amount presented less than 5% of total blood plasma ⍺-synuclein. Understanding this amount is particularly important for the eventual goal of measuring ⍺-synuclein in neuron-derived EVs as EVs that originate from a specific tissue like the brain are expected to be rare relative to EVs from blood cells, where ⍺-synuclein is also expressed. 

Importantly, in addition to their ultra-sensitive Simoa assay that enabled them to detect the normal unmodified ⍺-synuclein protein, they also developed an assay that is able to detect ⍺-synuclein that becomes phosphorylated at a specific site (pSer129) in the course of PD progression. “When we applied our advanced methodology to a cohort of blood samples obtained from patients with PD and Lewy Body Dementia as well as healthy control donors, we found that the ratio of phosphorylated ⍺-synuclein relative to total ⍺-synuclein was two to three-fold higher inside EVs relative to outside of EVs,” said Gilboa. “This was extremely exciting because it suggests that EVs may protect the phosphorylation state of proteins from circulating phosphatases that would otherwise erase this highly informative mark.” The team is now further exploring whether these assays could be used to differentiate PD patients from people without the disease.  

“The work by David Walt’s team presents a technological tour-de-force that brings us closer and closer to a next-generation diagnostic platform with extraordinary potential. At this point, we are not far from using these extremely rich and telling cell-derived vesicles as a window to peak into the brains of patients without requiring surgery,” said Wyss Founding Director Donald Ingber, M.D., Ph.D., who is also the Judah Folkman Professor of Vascular Biology at HMS and Boston Children’s Hospital and the Hansjörg Wyss Professor of Biologically Inspired Engineering at Harvard’s John A. Paulson School of Engineering and Applied Sciences.

Additional authors of the paper are George Church, Ph.D., a Wyss Core Faculty member and the Robert Winthrop Professor of Genetics at HMS and Alice Chen-Plotkin, M.D., the Parker Family Professor of Neurology at the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, who have both collaborated with Walt’s group since the inception of the EV project, as well as George Kannarkat. The work was supported by grants from the Michael J. Fox Foundation (Grant #2021A017224), Chan Zuckerberg Initiative NeuroDegeneration Challenge Network, and Good Ventures. Gilboa is an awardee of the Weizmann Institute of Science Women's Postdoctoral Career Development Award.

Media contact

Benjamin Boettner, Ph.D., Wyss Institute, Benjamin.Boettner@wyss.harvard.edu

###

The Wyss Institute for Biologically Inspired Engineering at Harvard University (www.wyss.harvard.edu) is a research and development engine for disruptive innovation powered by biologically-inspired engineering with visionary people at its heart. Our mission is to transform healthcare and the environment by developing ground-breaking technologies that emulate the way Nature builds and accelerate their translation into commercial products through formation of startups and corporate partnerships to bring about positive near-term impact in the world. We accomplish this by breaking down the traditional silos of academia and barriers with industry, enabling our world-leading faculty to collaborate creatively across our focus areas of diagnostics, therapeutics, medtech, and sustainability. Our consortium partners encompass the leading academic institutions and hospitals in the Boston area and throughout the world, including Harvard’s Schools of Medicine, Engineering, Arts & Sciences and Design, Beth Israel Deaconess Medical Center, Brigham and Women’s Hospital, Boston Children’s Hospital, Dana–Farber Cancer Institute, Massachusetts General Hospital, the University of Massachusetts Medical School, Spaulding Rehabilitation Hospital, Boston University, Tufts University, Charité – Universitätsmedizin Berlin, University of Zürich, and Massachusetts Institute of Technology.

 

END


[Attachments] See images for this press release:
Closing in on Parkinson’s Disease proteins in extracellular vesicles in the blood

ELSE PRESS RELEASES FROM THIS DATE:

Regional and global experts convene in Accra, Ghana to update cancer treatment guidelines for Sub-Saharan Africa

Regional and global experts convene in Accra, Ghana to update cancer treatment guidelines for Sub-Saharan Africa
2024-11-01
Accra, GHANA [October 29, 2024] — International oncology experts are gathering in Accra, Ghana for a series of meetings beginning today, to update cancer treatment recommendations in the NCCN Harmonized Guidelines™ for Sub-Saharan Africa. This is the latest event from a longstanding collaboration between the African Cancer Coalition (ACC), American Cancer Society (ACS), and National Comprehensive Cancer Network® (NCCN®), and the Clinton Health Access Initiative (CHAI) that collectively ...

China University of Geosciences (Beijing) unveils clues to an enigmatic geological process

China University of Geosciences (Beijing) unveils clues to an enigmatic geological process
2024-11-01
Cratons are fascinating yet enigmatic geological formations. Known to be relatively stable portions of the Earth’s continental crust, cratons have remained largely unchanged for billions of years. Although cratons have survived many geological events, some are undergoing decratonization—a process characterized by their deformation and eventual destruction. For example, the North China Craton (NCC), an ancient continental crust block, is known to have begun extensive decratonization during the Mesozoic era, largely due to tectonic and geochemical modifications and destabilization of its base (or ‘keel’). However, explaining the mechanisms ...

Fueling greener aviation with hydrogen

2024-11-01
Despite ongoing efforts to curb CO2 emissions with electric and hybrid vehicles, other forms of transportation remain significant contributors of greenhouse gases. To address this issue, old technologies are being revamped to make them greener, such as the reintroduction of sailing vessels in shipping and new uses for hydrogen in aviation. Now, researchers reporting in ACS Sustainable Chemistry & Engineering have used computer modeling to study the feasibility and challenges of hydrogen-powered aviation. “While there is a long way to go for hydrogen aviation to be realized at scale, we hope that our ...

Education, occupation, and wealth affect the risk of cognitive impairment

2024-11-01
Socioeconomic factors such as education, occupation, and wealth influence the likelihood of developing cognitive impairment or dementia in later life and whether a person is likely to recover, finds a new study led by UCL researchers. The research, published in Scientific Reports, followed 8,442 adults aged 50 and above in England over 10 years from 2008/09 to 2018/19, to examine how socioeconomic factors at the start of the study were associated with changes in cognitive status. The researchers tracked how these people moved between various states: healthy, mild cognitive impairment, and dementia. They also considered the possibility ...

Revealing causal links in complex systems

2024-11-01
Getting to the heart of causality is central to understanding the world around us. What causes one variable — be it a biological species, a voting region, a company stock, or a local climate — to shift from one state to another can inform how we might shape that variable in the future.  But tracing an effect to its root cause can quickly become intractable in real-world systems, where many variables can converge, confound, and cloud over any causal links.  Now, a team of MIT engineers hopes to provide some clarity in the pursuit of causality. They developed ...

Alzheimer disease as a clinical-biological construct— an international working group recommendation

2024-11-01
About The Study: This article discusses a recent revision of the Alzheimer Association criteria to define Alzheimer disease (AD) as a purely biological entity, which raises concerns that if diagnosis of AD can be reduced to the sole presence of AD core 1 biomarkers, major uncertainty and variability in the clinical prognosis of patients diagnosed with AD may be introduced. Corresponding Author: To contact the corresponding author, Bruno Dubois, MD, MSc, email bruno.dubois@aphp.fr. To access the embargoed study: Visit our For The Media website at this link https://media.jamanetwork.com/ (doi:10.1001/jamaneurol.2024.3770) Editor’s ...

Press registration now open for the EULAR 2025 Congress in Barcelona

2024-11-01
The EULAR 2025 Congress will gather the world's foremost rheumatology experts, fostering a unique environment to explore pioneering research, clinical advancements, and patient-centred innovations in rheumatology. This annual flagship event offers unparalleled access to transformative discussions and showcases the latest strides in patient care for rheumatic and musculoskeletal diseases (RMDs).    This year's Congress programme promises an impressive line-up, featuring must-see scientific sessions, EULAR Recommendations, and insightful abstract presentations. Esteemed speakers from across Europe and beyond ...

New research identifies ways to protect neurons from the negative effect of high-fat diet on multiple sclerosis progression

New research identifies ways to protect neurons from the negative effect of high-fat diet on multiple sclerosis progression
2024-11-01
NEW YORK, November 1, 2024 — Newly published research in the journal Glia has identified crucial links between dietary choices and the progression of multiple sclerosis (MS). The study, led by Patrizia Casaccia, founding director of the Advanced Science Research Center at the CUNY Graduate Center’s (CUNY ASRC) Neuroscience Initiative and Einstein Professor of Biology and Biochemistry at the CUNY Graduate Center, explored how enzymes called ceramide synthase 5 and 6 are responsible for the toxic effect ...

Boosting the nutritional value of black soldier fly larvae with biotechnology

Boosting the nutritional value of black soldier fly larvae with biotechnology
2024-11-01
With the rapid increase in the global population, a "protein crisis" is expected in the near future, where the supply of protein will not be able to meet the rising demand. Fishmeal is the most common protein source that supports the production of livestock and aquaculture products, which are key protein sources for human consumption. However, global shortage of fishmeal and its rising prices have created an urgent need to find and secure an alternative protein source. Insects are gaining attention as novel protein sources ...

Medication decisions in pregnancy: A balancing act

2024-11-01
Most women use medication during pregnancy. Yet, selecting appropriate drugs and doses is challenging. In a new The Lancet article, physicians and researchers from the Radboud university medical center, Maastricht UMC+, Imperial College London, and the University of Liverpool introduce a shared decision-making approach combining ethical principles and a pregnant woman’s values with existing evidence. They use the example of sertraline, a commonly prescribed antidepressant in pregnancy, to illustrate the advocated decision-making process. Although pregnant women often need medication, data on drug safety and efficacy in pregnancy remains limited. Historically seen as vulnerable research ...

LAST 30 PRESS RELEASES:

The Lancet: Deeply entrenched racial and geographic health disparities in the USA have increased over the last two decades—as life expectancy gap widens to 20 years

2 MILLION mph galaxy smash-up seen in unprecedented detail

Scientists find a region of the mouse gut tightly regulated by the immune system

How school eligibility influences the spread of infectious diseases: Insights for future outbreaks

UM School of Medicine researchers link snoring to behavioral problems in adolescents without declines in cognition

The Parasaurolophus’ pipes: Modeling the dinosaur’s crest to study its sound #ASA187

St. Jude appoints leading scientist to create groundbreaking Center of Excellence for Structural Cell Biology

Hear this! Transforming health care with speech-to-text technology #ASA187

Exploring the impact of offshore wind on whale deaths #ASA187

Mass General Brigham and BIDMC researchers unveil an AI protein engineer capable of making proteins ‘better, faster, stronger’

Metabolic and bariatric surgery safe and effective for patients with severe obesity

Smarter city planning: MSU researchers use brain activity to predict visits to urban areas

Using the world’s fastest exascale computer, ACM Gordon Bell Prize-winning team presents record-breaking algorithm to advance understanding of chemistry and biology

Jeffrey Hubbell joins NYU Tandon to lead new university-wide health engineering initiative & expand the school’s bioengineering focus

Fewer than 7% of global hotspots for whale-ship collisions have protection measures in place

Oldies but goodies: Study shows why elderly animals offer crucial scientific insights

Math-selective US universities reduce gender gap in STEM fields

Researchers identify previously unknown compound in drinking water

Chloronitramide anion – a newly characterized contaminant prevalent in chloramine treated tap water

Population connectivity shapes cultural complexity in chimpanzees

Direct hearing tests show that minke whales can hear high-frequency sounds

Whale-ship collision risk mapped across Earth’s oceans

Bye-bye microplastics: new plastic is recyclable and fully ocean-degradable

Unveiling nature of metal-support interaction: AI-driven breakthrough in catalysis

New imaging method enables detailed RNA analysis of the whole brain

Stability of perovskite solar cells doubled with protective coating

Chemists create world’s thinnest spaghetti

Empowering neuroscience: Large open brain models released

From traditional to technological: Advancements in fresco conservation

Design and imagination as essential tools during the climate crisis

[Press-News.org] Closing in on Parkinson’s Disease proteins in extracellular vesicles in the blood
Precision diagnostics for diseases that affect the brain and other organs brought closer by new ability to exclusively access contents of organ-derived extracellular vesicles in blood