��Ī - protein

Slow-moving shell of water can make Parkinson’s proteins ‘stickier’

sc604 — Tue, 15 Nov 2022 14:32:31 +0000

When attempting to discover potential treatments for protein misfolding diseases, researchers have primarily focused on the structure of the proteins themselves. However, researchers led by the ��Ī have shown that a thin shell of water is key to whether a protein begins to clump together, or aggregate, forming the toxic clusters which eventually kill brain cells.

Using a technique known as Terahertz spectroscopy, the researchers have shown that the movement of the water-based shell surrounding a protein can determine whether that protein aggregates or not. When the shell moves slowly, proteins are more likely to aggregate, and when the shell moves quickly, proteins are less likely to aggregate. The rate of movement of the shell is altered in the presence of certain ions, such as salt molecules, which are commonly used in the buffer solutions used to test new drug candidates.

The significance of the water shell, known as the hydration or solvation shell, in the folding and function of proteins has been strongly disputed in the past. This is the first time the solvation shell has been shown to play a key role in protein misfolding and aggregation, which could have profound implications in the search for treatments. The results are reported in the journal Angewandte Chemie International.

When developing potential treatments for protein misfolding diseases such as Parkinson’s and Alzheimer’s disease, researchers have been studying compounds which can prevent the aggregation of key proteins: alpha-synuclein for Parkinson’s disease or amyloid-beta for Alzheimer’s disease. To date however, there are no effective treatments for either condition, which affect millions worldwide.

“It’s the amino acids that determine the final structure of a protein, but when it comes to aggregation, the role of the solvation shell, which sits on the outside of a protein, has been overlooked until now,” said Professor Gabriele Kaminski Schierle from ��Ī’s Department of Chemical Engineering and Biotechnology, who led the research. “We wanted to know whether this water shell plays a role in protein behaviour – it’s been a question in the field for a while, but no one has been able to prove it.”

The solvation shell slides around on the surface of the protein, acting like a lubricant. “We wondered whether, if the movement of water molecules was slower in the solvation shell of a protein, it could slow the movement of the protein itself,” said Dr Amberley Stephens, the paper’s first author.

To test the role of the solvation shell in the aggregation of proteins, the researchers used alpha-synuclein, the key protein implicated in Parkinson’s disease. Using Teraheartz spectroscopy, a powerful technique to study the behaviour of water molecules, they were able to observe the movement of the water molecules that surround the alpha-synuclein protein.

They then added two different salts in solution to the proteins: sodium chloride (NaCl), or regular table salt, and cesium iodide (CsI). The ions in the sodium chloride – Na+ and Cl- – bind strongly to the hydrogen and oxygen ions in water, while the ions in the cesium iodide make much weaker bonds.

The researchers found that when the sodium chloride was added, the strong hydrogen bonds caused the movement of the water molecules in the solvation shell to slow down. This resulted in slower movement of the alpha-synuclein, and the aggregation rate increased. Conversely, when the cesium iodide was added, the water molecules sped up, and the aggregation rate decreased.

“In essence, when the water shell slows down, the proteins have more time to interact with each other, so they’re more likely to aggregate,” said Kaminski Schierle. “And on the flip side, when the solvation shell moves more quickly, the proteins become harder to catch, so they’re less likely to aggregate.”

“When researchers are screening for an aggregation inhibitor for Parkinson’s disease, they will usually use a buffer composition, but there’s been very little thought on how that buffer is interacting with the protein itself,” said Stephens. “Our results show that you need to understand the composition of the solvent inside the cell in order to mimic the conditions you have in the brain and ultimately end up with an inhibitor that works.”

“It’s so important to look at the whole picture, and that hasn’t been happening,” said Kaminski Schierle. “To effectively test whether a drug candidate will work in a patient, you need to mimic cellular conditions, which means you need to take everything into consideration, like salts and pH levels. The failure to look at the whole cellular environment has been limiting the field, which may be why we haven’t yet got an effective treatment for Parkinson’s disease.”

The research was supported in part by Wellcome, Alzheimer’s Research UK, the Michael J Fox Foundation, and the Medical Research Council (MRC), part of UK Research and Innovation (UKRI). Gabriele Kaminski Schierle is a Fellow of Robinson College, ��Ī.

Reference:
Amberley D Stephens et al. ‘Decreased Water Mobility Contributes to Increased α-Synuclein Aggregation.’ Angewandte Chemie International (2022). DOI: 10.1002/anie.202212063

Water – which makes up the majority of every cell in the body – plays a key role in how proteins, including those associated with Parkinson’s disease, fold, misfold, or clump together, according to a new study.

The failure to look at the whole cellular environment has been limiting the field, which may be why we haven’t yet got an effective treatment for Parkinson’s disease

Gabriele Kaminski Schierle

Sherbrooke Connectivity Imaging Lab via Getty

Corpus callosum, left-right connections, in a Parkinson's brain

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First Australians ate giant eggs of huge flightless birds

fpjl2 — Wed, 25 May 2022 15:09:43 +0000

Scientists settle debate surrounding 'Thunder bird' species, and whether its eggs were exploited by early Australian people around 50,000 years ago.

Following the hops of disordered proteins could lead to future treatments of Alzheimer’s disease

sc604 — Thu, 14 Jan 2021 16:09:45 +0000

Researchers from the ��Ī, Google Research and the University of Milan have used machine learning techniques to predict how proteins, particularly those implicated in neurological diseases, completely change their shapes in a matter of microseconds.

They found that when amyloid-beta, a key protein implicated in Alzheimer’s disease, adopts a collection of disordered shapes, it actually becomes less likely to stick together and form the toxic clusters which lead to the death of brain cells.

The results, reported in the journal Nature Computational Science, could aid in the future development of treatments for diseases involving disordered proteins, such as Alzheimer’s disease and Parkinson’s disease.

“We are used to thinking of proteins as molecules that fold into well-defined structures: finding out how this process happens has been a major research focus over the last 50 years,” said Professor Michele Vendruscolo from ��Ī’s Centre for Misfolding Diseases, who led the research. “However, about a third of the proteins in our body do not fold, and instead remain in disordered shapes, sort of like noodles in a soup.”

We do not know much about the behaviour of these disordered proteins, since traditional methods tend to address the problem of determining static structures, not structures in motion. The approach developed by the researchers harnesses the power of Google's cloud computing infrastructure to generate large numbers of short trajectories. “Extensive computer simulations allow us to capture the molecular-level motions of thousands of copies of a protein in parallel, and play them back like a movie,” said co-author Dr Kai Kohlhoff from Google Research.

The most common types of motions show up multiple times in these movies, making it possible to define the frequencies by which disordered proteins jump between different states.

“By counting these motions, we can predict which states the protein occupies and how quickly it transitions between them,” said first author Thomas Löhr from ��Ī’s Yusuf Hamied Department of Chemistry.

The researchers focused their attention on the amyloid-beta peptide, a protein fragment associated with Alzheimer’s disease, which aggregates to form amyloid plaques in the brains of affected individuals. They found that amyloid-beta hops between widely different states millions of times per second without ever stopping in any particular state. This is the hallmark of disorder, and the main reason for which amyloid-beta has been deemed ‘undruggable’ so far.

“The constant motion of amyloid-beta is one of the reasons it’s been so difficult to target – it’s almost like trying to catch smoke in your hands,” said Vendruscolo.

However, by studying a variant of amyloid-beta, in which one of the amino acids is modified by oxidation, the researchers obtained a glimpse on how to make it resistant to aggregation. They found that oxidated amyloid-beta changes shape even faster than its unmodified counterpart, providing a rationale to explain the decreased tendency for aggregation of the oxidated version.

“From a chemical perspective, this modification is a minor change. But the effect on the states and transitions between them is drastic,” said Löhr.

“By making disordered proteins even more disordered, we can prevent them from self-associating in aberrant manners,” said Vendruscolo.

The approach provides a powerful tool to investigate a class of proteins with fast and disordered motions, which have remained elusive so far despite their importance in biology and medicine.

Reference:
Thomas Löhr et al. ‘A kinetic ensemble of the Alzheimer's Aβ peptide’ Nature Computational Science (2021). DOI: 10.1038/s43588-020-00003-w

Study shows how to determine the elusive motions of proteins that remain disordered.

The constant motion of amyloid-beta is one of the reasons it’s been so difficult to target – it’s almost like trying to catch smoke in your hands

Michele Vendruscolo

NIH Image Gallery

Beta-Amyloid Plaques and Tau in the Brain

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Driving force behind cellular ‘protein factories’ could have implications for neurodegenerative disease

erh68 — Wed, 16 Dec 2020 19:00:00 +0000

In a study published today in Science Advances, researchers from the ��Ī show that tiny components within the cell are the biological engines behind effective protein production.

The endoplasmic reticulum (ER) is the cell’s protein factory, producing and modifying the proteins needed to ensure healthy cell function. It is the cell’s biggest organelle and exists in a web-like structure of tubes and sheets. The ER moves rapidly and constantly changes shape, extending across the cell to wherever it is needed at any given moment.

Using super-resolution microscopy techniques, researchers from ��Ī’s Department of Chemical Engineering and Biotechnology (CEB) have discovered the driving force behind these movements – a breakthrough that could have significant impact on the study of neurodegenerative diseases.

“It has been known that the endoplasmic reticulum has a very dynamic structure – constantly stretching and extending its shape inside the cell,” said Dr Meng Lu, research associate in the Laser Analytics Group, led by Professor Clemens Kaminski.

“The ER needs to be able to reach all places efficiently and quickly to perform essential housekeeping functions within the cell, whenever and wherever the need arises. Impairment of this capability is linked to diseases including Parkinson’s, Alzheimer’s, Huntington’s and ALS. So far there has been limited understanding of how the ER achieves these rapid and fascinating changes in shape and how it responds to cellular stimuli.”

Lu and colleagues discovered that another cell component holds the key – small structures, that look like tiny droplets contained in membranes, called lysosomes.

Lysosomes can be thought of as the cell’s recycling centres: they capture damaged proteins, breaking them down into their original building blocks so that they can be reused in the production of new proteins. Lysosomes also act as sensing centres – picking up on environmental cues and communicating these to other parts of the cell, which adapt accordingly.

There can be up to 1,000 or so lysosomes zipping around the cell at any one time and with them, the ER appears to change its shape and location, in an apparently orchestrated fashion.

What surprised the ��Ī scientists was their discovery of a causal link between the movement of the tiny lysosomes within the cell and the reshaping process of the large ER network.

“We could show that it is the movement of the lysosomes themselves that forces the ER to reshape in response to cellular stimuli,” said Lu. “When the cell senses that there is a need for lysosomes and ER to travel to distal corners of the cell, the lysosomes pull the ER web along with them, like tiny locomotives.”

From a biological point of view, this makes sense: The lysosomes act as a sensor inside the cell, and the ER as a response unit; co-ordinating their synchronous function is critical to cellular health.

To discover this surprising bond between two very different organelles, Kaminski’s research team made use of new imaging technologies and machine learning algorithms, which gave them unprecedented insights into the inner workings of the cell.

“It is fascinating that we are now able to look inside living cells and see the marvellous speed and dynamics of the cellular machinery at such detail and in real time,” said Kaminski. “Only a few years ago, watching organelles going about their business inside the cell would have been unthinkable.”

The researchers used illumination patterns projected onto living cells at high speed, and advanced computer algorithms to recover information on a scale more than one hundred times smaller than the width of a human hair. To capture such information at video rates has only recently become possible.

The researchers also used machine learning algorithms to extract the structure and movement of the ER networks and lysosomes in an automated fashion from thousands of datasets.

The team extended their research to look at neurons or nerve cells – specialised cells with long protrusions called axons along which signals are transmitted. Axons are extremely thin tubular structures and it was not known how the movement of the very large ER network is orchestrated inside these structures.

The study shows how lysosomes travel easily along the axons and drag the ER along behind them. The researchers also show how impairing this process is detrimental to the development of growing neurons.

Frequently, the researchers saw events where the lysosomes acted as repair engines for disconnected or broken pieces of ER structure, merging and fusing them into an intact network again. The work is therefore relevant for an understanding of disorders of the nervous system and its repair.

The team also studied the biological significance of this coupled movement, providing a stimulus – in this case nutrients – for the lysosomes to sense. The lysosomes were seen to move towards this signal, dragging the ER network behind so that the cell can elicit a suitable response.

“So far, little was known on the regulation of ER structure in response to metabolic signals,” said Lu. “Our research provides a link between lysosomes as sensors units that actively steer the local ER response.”

The team hopes that their insights will prove invaluable to those studying links between disease and cellular response, and their own next steps are focused on studying ER function and dysfunction in diseases such as Parkinson’s and Alzheimer’s.

Neurodegenerative disorders are associated with aggregation of damaged and misfolded proteins, so understanding the underlying mechanisms of ER function is critical to research into their treatment and prevention.

“The discoveries of the ER and lysosomes were awarded the Nobel Prize many years ago – they are key organelles essential for healthy cellular function,” said Kaminski. “It is fascinating to think that there is still so much to learn about this system, which is incredibly important to fundamental biomedical science looking to find the cause and cures of these devastating diseases.”

Reference:
Meng Lu et al. 'The structure and global distribution ofthe endoplasmic reticulum network is actively regulated by lysosomes.' Science Advances (2020). DOI: 10.1126/sciadv.abc7209

Researchers have identified the driving force behind a cellular process linked to neurodegenerative disorders such as Parkinson’s and motor neurone disease.

There is still so much to learn about this system, which is incredibly important to fundamental biomedical science

Clemens Kaminski

Inducing lysosome (green) anterograde motion with light leads to a rapid and significant extension of ER network (magenta).

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Women in STEM: Professor Laura Itzhaki

sc604 — Thu, 23 Jan 2020 07:00:00 +0000

My research sets out to use what scientists have learned from over half a century of research on proteins - the workhorses of the cell - to design new proteins to carry out pre-programmed functions. The intellectual challenge of protein engineering and of using redesigned proteins to dissect cellular pathways is what motivates me.

I spend my days thinking and breathing science, whether that is interacting with my research group in the Department of Pharmacology, writing papers and grants, discussing ideas and future projects with colleagues and collaborators, as well as undergraduate teaching and department administration.

No two days are the same. It’s the interaction with people and the intellectual challenge that makes the job so much fun. I try to spend one day a week at PolyProx Therapeutics, which is based at the Babraham Research Campus just a few miles from the city centre.

Two recent days in our group stand out. The first was when colleagues in my group showed proof of concept of our idea that we were hoping to patent and to spin out into a company. Based on my understanding of the underlying cellular mechanisms, I had been quietly confident that it would work, but I don’t think the rest of my group was until we got those first results! That was in the spring of 2017. A year later we were pitching to investors, and I have to say one of the happiest days of 2018 was when one of these investors said they liked what they’d heard and wanted to put some money in. Now, our research is supported by both research grants into my academic lab and investment into the company, and it is very exciting.

��Ī is a great place to be because of the wealth of scientists and commercialisation opportunities. I hope my research will lead to a new level of understanding of cellular quality control pathways that will allow us to harness them for therapeutic benefit. Ultimately I hope that the work in my academic group and in PolyProx Therapeutics will lead to new drugs for diseases such as cancer.

My advice for women considering a career in a STEM field is to go for it! Know that you can have a career and do the other things you might want out of life such as having a family.

Professor Laura Itzhaki is a group leader in the Department of Pharmacology and a Fellow of Newnham College. Here, she tells us about forming her own spin-out company, pitching to investors and her research on the 'workhorses' of the cell.

Yes

Study highlights potential for ‘liquid health check’ to predict disease risk

cjb250 — Mon, 02 Dec 2019 16:00:36 +0000

Preventative medicine programmes such as the UK National Health Service’s Health Check and Healthier You programmes are aimed at improving our health and reducing our risk of developing diseases. While such strategies are inexpensive, cost effective and scalable, they could be made more effective using personalised information about an individual’s health and disease risk.

The rise and application of ‘big data’ in healthcare, assessing and analysing detailed, large-scale datasets makes it increasingly feasible to make predictions about health and disease outcomes and enable stratified approaches to prevention and clinical management.

Now, an international team of researchers from the UK and USA, working with biotech company SomaLogic, has shown that large-scale measurement of proteins in a single blood test can provide important information about our health and can help to predict a range of different diseases and risk factors.

Our bodies contain around 30,000 different proteins, which are coded for by our DNA and regulate biological processes. Some of these proteins enter the blood stream by purposeful secretion to orchestrate biological processes in health or in disease, for example hormones, cytokines and growth factors. Others enter the blood through leakage from cell damage and cell death. Both secreted and leaked proteins can inform health status and disease risk.

In a proof-of-concept study based on five observational cohorts in almost 17,000 participants, researchers scanned 5,000 proteins in a plasma sample taken from each participant. Plasma is the single largest component of blood and is the clear liquid that remains after the removal of red and white blood cells and platelets. The study resulted in around 85 million protein targets being measured.

The technique involves using fragments of DNA known as aptamers that bind to the target protein. In general, only specific fragments will bind to particular proteins – in the same way that only a specific key will fit in a particular lock. Using existing genetic sequencing technology, the researchers can then search for the aptamers and determine which proteins are present and in what concentrations.

The researchers analysed the results using statistical methods and machine learning techniques to develop predictive models – for example, that an individual whose blood contains a certain pattern of proteins is at increased risk of developing diabetes. The models covered a number of health states, including levels of liver fat, kidney function and visceral fat, alcohol consumption, physical activity and smoking behaviour, and for risk of developing type 2 diabetes and cardiovascular disease.

The accuracy of the models varied, with some showing high predictive powers, such as for percentage body fat, while others had only modest prognostic power, such as for cardiovascular risk. The researchers report that their protein-based models were all either better predictors than models based on traditional risk factors or would constitute more convenient and less expensive alternatives to traditional testing.

Many of the proteins are linked to a number of health states or conditions; for example, leptin, which modulates appetite and metabolism, was informative for predictive models of percentage body fat, visceral fat, physical activity and fitness.

One difference between genome sequencing and so-called ‘proteomics’ – studying an individual’s proteins in depth – is that whereas the genome is fixed, the proteome changes over time. It might change as an individual becomes more obese, less physically active or smokes, for example, so proteins will be able to track changes in an individual's health status over a lifetime.

“Proteins circulating in our blood are a manifestation of our genetic make-up as well as many other factors, such as behaviours or the presence of disease, even if not yet diagnosed,” said Dr Claudia Langenberg, from the MRC Epidemiology Unit at the ��Ī. “This is one of the reasons why proteins are such good indicators of our current and future health state and have the potential to improve clinical prediction across different and diverse diseases.”

“It’s remarkable that plasma protein patterns alone can faithfully represent such a wide variety of common and important health issues, and we think that this is just the tip of the iceberg,” said Dr Stephen Williams, Chief Medical Officer of SomaLogic, who led the study. “We have more than a hundred tests in our SomaSignal pipeline and believe that large-scale protein scanning has the potential to become a sole information source for individualised health assessments.”

While this study shows a proof-of-principle, the researchers say that as technology improves and becomes more affordable, it is feasible that a comprehensive health evaluation using a battery of protein models derived from a single blood sample could be offered as routine by health services.

“This proof of concept study demonstrates a new paradigm that measurement of blood proteins can accurately deliver health information that spans across numerous medical specialties and that should be actionable for patients and their healthcare providers,” said Peter Ganz, MD, co-leader of this study and the Maurice Eliaser Distinguished Professor of Medicine at the UCSF and Director of the Center of Excellence in Vascular Research at Zuckerberg San Francisco General Hospital and Trauma Center. “I expect that in the future we will look back at this Nature Medicine proteomic study as a critical milestone in personalising and thus improving the care of our patients.”

Reference
Williams, SA et al. Plasma protein patterns as comprehensive indicators of health; Nat Med; 2 Dec 2019; DOI: 10.1038/s41591-019-0665-2

Competing interests
The research was a collaboration with SomaLogic Inc, which has a commercial interest in the results. Several co-authors were or are employees of SomaLogic. The company has provided funding to the ��Ī. Dr Peter Ganz is a member of the SomaLogic Medical Advisory board, for which he receives no remuneration of any kind.

Funding
The research was supported by the UK Medical Research Council, US National Institutes on Aging, British Heart Foundation, National Institute for Health Research, the Norwegian Ministry of Health, Norwegian University of Science and Technology and Norwegian Research Council, Central Norway Regional Health Authority, Nord-Trondelag County Council, Norwegian Institute of Public Health, US National Heart, Lung and Blood Institute. SomaScan assays and the Covance study were funded by SomaLogic, Inc.

Proteins in our blood could in future help provide a comprehensive ‘liquid health check’, assessing our health and predicting the likelihood that we will we will develop a range of diseases, according to research published today in Nature Medicine.

Proteins circulating in our blood are a manifestation of our genetic make-up as well as many other factors, such as behaviours or the presence of disease, even if not yet diagnosed

Claudia Langenberg

Geralt

Blood plasma

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��Ī spin-out company wins £18m to fight Alzheimer's

plc32 — Thu, 24 Jan 2019 10:27:38 +0000

A biopharmaceutical company set-up by ��Ī academics from St John's College to develop drugs to treat illnesses such as Alzheimer's, Parkinson’s and more than 50 other related diseases has won £18 million in a Series A financing round.

Wren Therapeutics raised the funding from an international syndicate led by The Baupost Group with participation from LifeForce Capital and a number of high net worth individual investors.

Several of the company’s scientific founders are members of St John’s, including Professor Sir Christopher Dobson, Master of St John's, Professor Tuomas Knowles, a St John's Fellow, and Dr Samuel Cohen, the St John’s Entrepreneur in Residence.

Wren Therapeutics focuses on drug discovery and development for protein misfolding diseases such as Alzheimer’s and Parkinson’s and was founded in 2016.

Protein molecules form the machinery which carry out all of the executive functions in living systems. However, proteins sometimes malfunction and become misfolded, leading to a complex chain of molecular events that can cause long-lasting damage to the health of people affected and may ultimately lead to death.

This group of medical disorders are known as protein misfolding diseases. Alzheimer’s and Parkinson’s are widely recognised protein misfolding diseases, but others include type-2 diabetes, motor neurone disease and more than 50 other related illnesses.

Dr. Cohen explained: “Protein misfolding diseases are one of the most critical global healthcare challenges of the 21st century but are highly complex and challenging to address. Current strategies - in particular those driven by traditional drug discovery and biological approaches - have proven, at least to date, to be ineffective.

“Wren’s new and unique approach is instead built on concepts from the physical sciences and focuses on the chemical kinetics of the protein misfolding process, creating a predictive and quantitatively driven platform that has the potential to radically advance drug discovery in this class of diseases.”

Wren Therapeutics is a spin-off company from the ��Ī and Lund University in Sweden. The company is based at the ��Ī, in the recently opened Chemistry of Health Centre, and plans on opening a satellite office in Boston, Massachusetts.

Professor Sir Christopher Dobson said: "Wren is built on many years of highly collaborative, uniquely integrated, interdisciplinary research that has uncovered the key molecular mechanisms associated with protein misfolding diseases.

"I am hugely enthusiastic about our ability to make tangible progress against these diseases and change the course of life for millions of people around the world suffering from these debilitating and increasingly common medical disorders.”

The company will announce its board of directors shortly.

Wren Therapeutics secures £18 million in funding to tackle protein misfolding diseases.

"I am hugely enthusiastic about our ability to make tangible progress against these diseases"

Professor Sir Christopher Dobson

Dr Samuel Cohen, Entrepreneur in Residence at St John's and CEO of Wren Therapeutics

Yes

New imaging technique measures toxicity of proteins associated with Alzheimer’s and Parkinson’s diseases

sc604 — Wed, 23 Nov 2016 09:57:57 +0000

Researchers have developed a new imaging technique that makes it possible to study why proteins associated with Alzheimer’s and Parkinson’s diseases may go from harmless to toxic. The technique uses a technology called multi-dimensional super-resolution imaging that makes it possible to observe changes in the surfaces of individual protein molecules as they clump together. The tool may allow researchers to pinpoint how proteins misfold and eventually become toxic to nerve cells in the brain, which could aid in the development of treatments for these devastating diseases.

The researchers, from the ��Ī, have studied how a phenomenon called hydrophobicity (lack of affinity for water) in the proteins amyloid-beta and alpha synuclein – which are associated with Alzheimer’s and Parkinson’s respectively – changes as they stick together. It had been hypothesised that there was a link between the hydrophobicity and toxicity of these proteins, but this is the first time it has been possible to image hydrophobicity at such high resolution. Details are reported in the journal Nature Communications.

“These proteins start out in a relatively harmless form, but when they clump together, something important changes,” said Dr Steven Lee from ��Ī’s Department of Chemistry, the study’s senior author. “But using conventional imaging techniques, it hasn’t been possible to see what’s going on at the molecular level.”

In neurodegenerative diseases such as Alzheimer’s and Parkinson’s, naturally-occurring proteins fold into the wrong shape and clump together into filament-like structures known as amyloid fibrils and smaller, highly toxic clusters known as oligomers which are thought to damage or kill neurons, however the exact mechanism remains unknown.

For the past two decades, researchers have been attempting to develop treatments which stop the proliferation of these clusters in the brain, but before any such treatment can be developed, there first needs to be a precise understanding of how oligomers form and why.

“There’s something special about oligomers, and we want to know what it is,” said Lee. “We’ve developed new tools that will help us answer these questions.”

When using conventional microscopy techniques, physics makes it impossible to zoom in past a certain point. Essentially, there is an innate blurriness to light, so anything below a certain size will appear as a blurry blob when viewed through an optical microscope, simply because light waves spread when they are focused on such a tiny spot. Amyloid fibrils and oligomers are smaller than this limit so it’s very difficult to directly visualise what is going on.

However, new super-resolution techniques, which are 10 to 20 times better than optical microscopes, have allowed researchers to get around these limitations and view biological and chemical processes at the nanoscale.

Lee and his colleagues have taken super-resolution techniques one step further, and are now able to not only determine the location of a molecule, but also the environmental properties of single molecules simultaneously.

Using their technique, known as sPAINT (spectrally-resolved points accumulation for imaging in nanoscale topography), the researchers used a dye molecule to map the hydrophobicity of amyloid fibrils and oligomers implicated in neurodegenerative diseases. The sPAINT technique is easy to implement, only requiring the addition of a single transmission diffraction gradient onto a super-resolution microscope. According to the researchers, the ability to map hydrophobicity at the nanoscale could be used to understand other biological processes in future.

The research was supported by the Medical Research Council, the Engineering and Physical Sciences Research Council, the Royal Society and the Augustus Newman Foundation.

Reference
Marie N. Bongiovanni et al. ‘Multi-dimensional super-resolution imaging enables surface hydrophobicity mapping.’ Nature Communications (2016). DOI: 10.1038/NCOMMS13544

A new super-resolution imaging technique allows researchers to track how surface changes in proteins are related to neurodegenerative diseases such as Alzheimer’s and Parkinson’s diseases.

These proteins start out in a relatively harmless form, but when they clump together, something important changes.

Steven Lee

ZEISS Microscopy

Brain showing hallmarks of Alzheimer's disease (plaques in blue)

The text in this work is licensed under a Creative Commons Attribution 4.0 International License. For image use please see separate credits above.

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�������������Ī - protein

Slow-moving shell of water can make Parkinson’s proteins ‘stickier’

First Australians ate giant eggs of huge flightless birds

Following the hops of disordered proteins could lead to future treatments of Alzheimer’s disease

Driving force behind cellular ‘protein factories’ could have implications for neurodegenerative disease

Women in STEM: Professor Laura Itzhaki

Study highlights potential for ‘liquid health check’ to predict disease risk

�������������Ī spin-out company wins £18m to fight Alzheimer's

New imaging technique measures toxicity of proteins associated with Alzheimer’s and Parkinson’s diseases

��Ī - protein

��Ī spin-out company wins £18m to fight Alzheimer's