Researchers from the University of Pennsylvania School of Medicine have shown, in unprecedented detail, how a small molecule is able to selectively take apart abnormally folded protein fibers connected to Alzheimer's disease and prion diseases. The findings appear online this week in the Proceedings of the National Academy of Sciences. Finding a way to dismantle misfolded proteins has implications for new treatments for a host of neurodegenerative diseases.
Abnormal accumulation of amyloid fibers and other misfolded forms in the brain cause neurodegenerative diseases. Similarly, build-up of abnormally folded prion proteins between neurons causes the human version of mad cow disease, Creutzfeldt-Jakob disease.
“Surprisingly, a small molecule called DAPH selectively targets the areas that hold fibers together, and converts fibers to a form that is unable to grow. Normally fibers grow from their ends, but the drug stops this activity,” says senior author James Shorter, PhD, Assistant Professor of Biochemistry and Biophysics. “Our data suggest that it is possible to generate effective small molecules that can attack amyloid fibers, which are associated with so many devastating diseases.”
The researchers are now working on how DAPH acts as a wedge to stop the fibers from growing. “Presumably DAPH fits very neatly into the crevices between fiber subunits,” explains Shorter. “When we grow yeast cells with the prion in the presence of DAPH, they begin to lose the prion. We also saw this in the test tube using pure fibers. The small molecule directly remodels fiber architecture. We’ve really been able to get at the mechanism by which DAPH, or any small molecule, works for the first time.” DAPH was originally found in a screen of small molecules that reduce amyloid-beta toxicity in the lab of co-author Vernon Ingram, Shorter’s collaborator at the Massachusetts Institute of Technology (MIT).
In a test tube, if a small amount of amyloid or prion fiber is added to the normal form of the protein, it converts it to the fiber form. But when DPAH is added to the mix, the yeast prion protein does not aggregate into fibers. “It’s essentially stopping fiber formation in its tracks,” says Huan Wang, first author and research specialist in Shorter’s lab. “We were surprised to see two very different proteins, amyloid-beta and Sup35, sensitive to this same small molecule.”
The next step is to identify more potent DAPH variants with greater selectivity for deleterious amyloids. Since some amyloids may turn out to be beneficial – for example, one form may be involved in long-term memory formation – it will be necessary to find a drug that does not hit all amyloids indiscriminately. “We’d need one that hits only problem amyloids, and DAPH gives us a hint that such selectivity is possible” says Shorter.
This work was initiated in Susan Lindquist’s lab at MIT and completed at Penn. The study was funded by the National Institute of General Medical Sciences, the Alzheimer’s Association, the Kurt and Johanna Immerwahr Fund for Alzheimer Research, a DuPont-MIT alliance, the American Heart Association, and pilot grants from the University of Pennsylvania Alzheimer’s Disease Core Center and Institute on Aging.
PENN Medicine is a $3.5 billion enterprise dedicated to the related missions of medical education, biomedical research, and excellence in patient care. PENN Medicine consists of the University of Pennsylvania School of Medicine (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System.
Penn's School of Medicine is currently ranked #4 in the nation in U.S.News & World Report's survey of top research-oriented medical schools; and, according to most recent data from the National Institutes of Health, received over $379 million in NIH research funds in the 2006 fiscal year. Supporting 1,400 fulltime faculty and 700 students, the School of Medicine is recognized worldwide for its superior education and training of the next generation of physician-scientists and leaders of academic medicine.
The University of Pennsylvania Health System includes three hospitals — its flagship hospital, the Hospital of the University of Pennsylvania, rated one of the nation’s “Honor Roll” hospitals by U.S.News & World Report; Pennsylvania Hospital, the nation's first hospital; and Penn Presbyterian Medical Center — a faculty practice plan; a primary-care provider network; two multispecialty satellite facilities; and home care and hospice.
Karen Kreeger | newswise
New photocatalyst speeds up the conversion of carbon dioxide into chemical resources
29.05.2017 | DGIST (Daegu Gyeongbuk Institute of Science and Technology)
Copper hydroxide nanoparticles provide protection against toxic oxygen radicals in cigarette smoke
29.05.2017 | Johannes Gutenberg-Universität Mainz
The world's highest gain high power laser amplifier - by many orders of magnitude - has been developed in research led at the University of Strathclyde.
The researchers demonstrated the feasibility of using plasma to amplify short laser pulses of picojoule-level energy up to 100 millijoules, which is a 'gain'...
Staphylococcus aureus is a feared pathogen (MRSA, multi-resistant S. aureus) due to frequent resistances against many antibiotics, especially in hospital infections. Researchers at the Paul-Ehrlich-Institut have identified immunological processes that prevent a successful immune response directed against the pathogenic agent. The delivery of bacterial proteins with RNA adjuvant or messenger RNA (mRNA) into immune cells allows the re-direction of the immune response towards an active defense against S. aureus. This could be of significant importance for the development of an effective vaccine. PLOS Pathogens has published these research results online on 25 May 2017.
Staphylococcus aureus (S. aureus) is a bacterium that colonizes by far more than half of the skin and the mucosa of adults, usually without causing infections....
Physicists from the University of Würzburg are capable of generating identical looking single light particles at the push of a button. Two new studies now demonstrate the potential this method holds.
The quantum computer has fuelled the imagination of scientists for decades: It is based on fundamentally different phenomena than a conventional computer....
An international team of physicists has monitored the scattering behaviour of electrons in a non-conducting material in real-time. Their insights could be beneficial for radiotherapy.
We can refer to electrons in non-conducting materials as ‘sluggish’. Typically, they remain fixed in a location, deep inside an atomic composite. It is hence...
Two-dimensional magnetic structures are regarded as a promising material for new types of data storage, since the magnetic properties of individual molecular building blocks can be investigated and modified. For the first time, researchers have now produced a wafer-thin ferrimagnet, in which molecules with different magnetic centers arrange themselves on a gold surface to form a checkerboard pattern. Scientists at the Swiss Nanoscience Institute at the University of Basel and the Paul Scherrer Institute published their findings in the journal Nature Communications.
Ferrimagnets are composed of two centers which are magnetized at different strengths and point in opposing directions. Two-dimensional, quasi-flat ferrimagnets...
24.05.2017 | Event News
23.05.2017 | Event News
22.05.2017 | Event News
29.05.2017 | Earth Sciences
29.05.2017 | Life Sciences
29.05.2017 | Physics and Astronomy