CELL DEATH PROTEINS KEY TO FIGHTINING DISEASE

Melbourne researchers have uncovered key steps involved in programmed cell death, offering new targets for the treatment of diseases including lupus, cancers and neurodegenerative diseases

The research teams from the Walter and Eliza Hall Institute worked together to discover the three-dimensional structure of a key cell death protein called Bak and reveal the first steps in how it causes cell death. Their studies were published in Molecular Celland Proceedings of the National Academy of Sciences.

Programmed cell death, known as apoptosis, occurs naturally when the body has to remove unwanted cells. Chemical signals tell the cell to die by activating the apoptosis proteins Bak and Bax, which break down the 'energy factory' of the cell, known as the mitochondria. When this process goes awry, defective cells such as cancer cells can continue to live, or healthy cells can die unnecessarily, such as occurs in Alzheimer's disease.

Visualizing death proteins

Using the Australian Synchrotron, Mr Jason Brouwer, Dr Peter Czabotar, Dr Ruth Kluck and colleagues from the institute's Structural Biology division investigated how the structure of Bak changes in order to initiate cell death. The research was published in Molecular Cell.

"Understanding the way cell death proteins work and what they look like is crucial to finding new ways to treat disease," Dr Czabotar said. "Our research showed how Bak morphs from one shape to another to trigger apoptosis. Once Bak becomes 'activated' within the cell, it couples with another Bak molecule to form a 'dimer', which then goes on to initiate apoptosis."

Dr Czabotar said understanding apoptosis would allow researchers to develop new ways to treat disease. "Knowing the structure of these proteins and how they work in the cell is essential in designing new treatments to fight disease."

Seeking the hole story

Dr Dana Westphal, Dr Kluck, Dr Grant Dewson, Professor Jerry Adams and colleagues from the Molecular Genetics of Cancer and Cell Signalling and Cell Death divisions examined how the Bak and Bax dimers attach to mitochondria and perforate them. The research was published in Proceedings of the National Academy of Sciences.

Dr Kluck said dimers of Bak and Bax break open the mitochondrial surface, but the mechanism remains poorly understood. "A crucial stage of apoptosis is the release of key proteins from within the mitochondria," she said. "Scientists thought this happened by Bak and Bax poking through the mitochondrial membrane to form a hole, but our work has shown this doesn't happen. Instead, these proteins collapse onto the oily surface of the mitochondria and crowd the surface until holes form."

"We and others are now working to discover exactly how these proteins come together to destroy the mitochondria and trigger apoptosis. A deeper understanding of this pivotal event is likely to suggest new ways to regulate apoptosis to combat disease."

 

Prion Proteins The Sci Fi Villains Behind Mad Cow Disease And Human Chronic Nerve Problems

Today's post from media.uzh.ch (see link below) may seem light years away from the sorts of neuropathy we experience every day but in fact is much closer than you think. With all these things, you have to continually remind yourself exactly what neuropathy is:- damage to the nerves. There are dozens of causes and dozens of types but nerve damage leads to the symptoms we most frequently feel. This fascinating article brings images from the 90's of cows struggling to stay on their feet under the same general umbrella description as the tingling and burning we suffer from when we report our symptoms to our doctors. Scientists are seemingly just beginning to scratch the surface of the knowledge that concludes that certain proteins can be responsible for all this strange behaviour in our nervous systems. It's fascinating and frightening at the same time but you do get the feeling that we're on the point of huge scientific discoveries regarding neuropathy and that can only be a good thing as we struggle with drug treatments that clearly only work to a limited extent. Worth a read - fascinating stuff!

Impact of prion proteins on the nerves revealed for the first time
News release, 8 August 2016 
 
When prion proteins mutate, they trigger mad cow and Creutzfeldt-Jakob disease. Although they are found in virtually every organism, the function of these proteins remained unclear. Researchers from the University of Zurich and the University Hospital Zurich now demonstrate that prion proteins, coupled with a particular receptor, are responsible for nerve health. The discovery could yield novel treatments for chronic nerve diseases.


Without the prion proteins, the so-called Schwann cells around the sensitive nerve fibers no longer form an insulating layer to protect the nerves. (Image: NatureReview / Neuroscience)

Ever since the prion gene was discovered in 1985, its role and biological impact on the neurons has remained a mystery. “Finally, we can ascribe a clear-cut function to prion proteins and reveal that, combined with particular receptor, they are responsible for the long-term integrity of the nerves,” says Professor Adriano Aguzzi from the Neuropathological Institute at the University of Zurich and University Hospital Zurich. The present study therefore clears up a question that researchers have been puzzling over for 30 years, but ultimately went unanswered.

Prions are dangerous pathogens that trigger fatal brain degeneration in humans and animals. In the 1990s, they were responsible for the BSE epidemic more commonly known as mad cow disease. In humans, they cause Creutzfeldt-Jakob disease and other neurological disorders that are fatal and untreatable. Meanwhile, we know that infectious prions consist of a defectively folded form of a normal prion protein called PrPC located in the neuron membrane. The infectious prions multiply by kidnapping PrPC and converting it into other infectious prions. 

Absent prion proteins cause nerve diseases

For a long time, it remained unclear why we humans – like most other organisms – have a protein in our neurons that does not perform any obvious function, yet can be extremely dangerous. Aguzzi has spent decades researching this issue and examining the theory that animals without the PrPC gene are resistant to prion diseases. But what are the repercussions for the organism if the prion protein is deactivated?

A few years ago, Aguzzi and his team discovered that mice without the PrPC gene suffer from a chronic disease of the peripheral nervous system. The reason: The so-called Schwann cells around the sensitive nerve fibers no longer form an insulating layer to protect the nerves. Due to this insulating myelin deficit, the peripheral nerves become diseased, potentially resulting in motoric disorders in the motion tract and paralysis.

The researchers have now gone one step further in the lab: In a new study, Alexander Küffer and Asvin Lakkaraju clarify exactly why the peripheral nerves become damaged in the absence of the prion protein PrPC. They discovered how the PrPC produced by the neurons docks onto the Schwann cells: namely via a receptor called Gpr126. If the prion protein and the receptor work together, a particular messenger substance (cAMP) which regulates the chemical interaction in the cells and is essential for the integrity of the nerve’s protective sheath increases. Gpr126 belongs to the large family of “G-protein-coupled receptors”, which are involved in many physiological processes and diseases.

30-year-old research question finally answered

This discovery solves a key question that has long puzzled neuroscientists and points towards future applications in hospitals. “If you want to deactivate the prion protein PrPC fully for potential Creutzfeld-Jakob disease treatments, you need to know the potential side effects on the nerves in the future,” explains Aguzzi. Moreover, the present results on the effect of PrPC at molecular level could yield a new approach for peripheral neuropathy. Currently, there are only extremely limited therapeutic options for these chronic debilitating diseases of the nervous system.
Literature:

Alexander Küffer, Asvin K. K. Lakkaraju, Amit Mogha, Sarah C. Petersen, Kristina Airich, Cédric Doucerain, Rajlakshmi Marpakwar, Pamela Bakirci, Assunta Senatore, Arnaud Monnard, Carmen Schiavi, Mario Nuvolone, Bianka Grosshans, Simone Hornemann, Frederic Bassilana, Kelly R. Monk & Adriano Aguzzi. The prion protein is an agonistic ligand of the G-protein-coupled receptor Gpr1/Adgrg6. Nature, 8 August 2016. doi:10.1038/nature19312

http://www.media.uzh.ch/en/Press-Releases/2016/Prion-Proteine.html