We need our researchers following up with this new understanding and apply it to the neuronal cascade of death.
http://www.alphagalileo.org/ViewItem.aspx?ItemId=134152&CultureCode=en
Scientists in Melbourne, Australia, have revealed the structure of a
protein that is essential for triggering a form of programmed cell death
called necroptosis, making possible the development of new drugs to
treat chronic inflammatory diseases such as Crohn’s disease and
rheumatoid arthritis.
Dr James Murphy, Associate Professor John Silke, Dr Joanne
Hildebrand, Dr Peter Czabotar, Professor Warren Alexander and colleagues
from the Walter and Eliza Hall Institute have shown that the protein
MLKL plays a crucial role in the signalling pathways that trigger a
recently discovered cell death pathway called necroptosis. The results
were published today in the journal Immunity.
Usually, when a cell detects that it is infected by a virus or
bacteria or has other irreparable damage it self-destructs through a
process called apoptosis. But Associate Professor Silke said some
bacteria and viruses had developed ways of preventing this cell suicide,
also allowing the invaders to survive. It is at this point that the
‘back up’ necroptosis pathway might be activated.
“During necroptosis the cell still self-destructs but in doing so it
also sends an ‘SOS’ to the immune system to tell it that something has
gone wrong with the cell’s normal cell death process of apoptosis. So
internally, the cell is still doing its best to self-destruct in an
orderly and programmed way, but it is simultaneously sending signals to
the immune system to mount a response to the invaders.”
However there are times when the necroptosis pathway may be
inappropriately activated, sending messages to the immune system that
promote inflammation and the development of inflammatory diseases.
Dr Murphy said the discovery of MLKL’s role in activating the
necroptosis pathway was an important step in understanding this cell
death pathway and its role in disease. “Necroptosis has only been
defined in the past 10 years and the role MLKL plays was only discovered
in 2012,” Dr Murphy said. “This study provides the first genetic proof
that MLKL is required for necroptosis as well as the first full-length,
atomic level, three-dimensional structure of a protein that regulates
necroptosis. These discoveries are really exciting because they give us a
new target to look at for developing treatments for people who suffer
from an inflammatory disease.”
The three-dimensional images of MLKL, which were obtained using the
Australian Synchrotron, revealed an interesting detail about the
protein, Dr Murphy said. “The structure revealed that MLKL is a ‘dead
enzyme’, making it different from the other proteins in the signalling
pathway,” Dr Murphy said. “We discovered that MLKL needs to be ‘switched
on’ before it can activate necroptosis. MLKL could therefore be a
perfect target for treatments because it is different from almost every
other cell-signalling protein, making it easier to develop highly
specific drugs and limiting potential side effects.”
Associate Professor Silke said the team was now trying to determine
the ‘on’ and ‘off’ states of MLKL and how it could be modified to treat
disease. “We are now trying to work out what MLKL looks like at the
atomic level when it is switched ‘on’ so that we can begin to develop
drugs that will block it,” Associate Professor Silke said. “We are
excited about this fundamental discovery and, with colleagues at the
institute, we are already using this knowledge to develop specific,
drug-like molecules to test in disease models. This could directly lead
to treatments that will help patients who have chronic inflammatory
diseases including rheumatoid arthritis, inflammatory bowel syndrome,
Crohn’s disease and psoriasis.”
The research was supported by the Australian National Health and
Medical Research Council, Australian Research Council and the Victorian
Government.
http://www.wehi.edu.au/site/latest_news/cell_death_protein_could_offer_new_anti-inflammatory_drug_target
No comments:
Post a Comment