The findings provide a "testable translational hypothesis" as to the development and progression of PSP and may also provide clues into other more common brain disorders brought about by accumulation of tau protein in the brain, researchers say. Those "tauopathies" include some forms of Parkinson's disease, frontotemporal dementia, Alzheimer's disease, and other disorders.
"These are promising gene candidates that may help us understand and potentially treat PSP," says neuropathologist Dennis W. Dickson, M.D., a study co-lead author. "While these findings are surprisingly robust, we are still at the very earliest stages of this work. These are excellent candidate genes, but we have to make sure they are true susceptibility genes."
With 29 institutions represented from the United States and Europe, the study is one of the largest international collaborations to date researching PSP, Dr. Dickson says. It is also one of the largest reports on a pathologically confirmed neurological disorder.
Mayo Clinic's contribution was pivotal, he says. With its focus on movement disorders, Mayo Clinic in Florida is a national center for referral of patients with PSP for diagnosis, treatment, and research. It also has the world's largest collection of brain tissue from PSP patients. The 10-year-old Society for Progressive Supranuclear Palsy Brain Bank, established by Dr. Dickson, contains tissue samples from more than 800 patients with PSP. Medical institutions around the country routinely send autopsy tissues to the Mayo PSP brain bank.
Mayo Clinic contributed over 600 of the 1,114 PSP DNA samples used in the first half of the study; the other international institutions contributed the rest.
To search for susceptibility genes, the research team conducted a genome-wide association study (GWAS), which examines the differences between the genomes of patients with a certain disease compared to a control group of participants without the disease. This is done by looking at single nucleotide polymorphisms (SNPs, pronounced snips), which are DNA sequence variations that can occur in genes or in the non-coding regions between genes.
Researchers first assessed association between genotypes at 531,451 SNPs in the group of 1,114 PSP DNA samples, and in blood from a control group of 3,247 participants who did not have PSP. The SNPs "hits" they found were then tested in a second group: blood samples from 1,051 living PSP patients and blood from a second group of 3,560 control participants. For that phase of the study, Mayo Clinic in Florida contributed blood from about 200 PSP patients.
In addition to finding that PSP patients had variants in their tau gene, which was expected, the researchers also found the three SNPs that appear to be candidate PSP genes. All three have neurological functions. MOBP is a protein associated with myelin, an insulating material that forms a sheath around the axon of nerves. Glial cells form myelin, and these cells are affected in PSP. STX6 is a gene involved in recycling the membrane of a neuron, and membrane recycling has been implicated in a number of neurodegenerative diseases, including Alzheimer's, according to Dr. Dickson. The third gene, EIF2AK3, is involved in translating RNA to protein, and it signals cells to stop making proteins when abnormal proteins start to accumulate inside cells — as they do in neurons when tau errantly builds up.
Variants in these three genes were also found in the two control populations, but were significantly higher in the PSP patients (both brain samples and PSP blood samples). That suggests these genes do not cause PSP, but contribute to a person's susceptibility to the disease, he says.
"We don't know for sure that these SNPs are precisely at these gene locations," says Dr. Dickson. "If they are real PSP susceptibility genes, we can then zero in on variants that have an impact on the disease, which might then be exploited therapeutically.
"While we are a long way from any new treatment, this new research is exciting for researchers who are dedicated to understanding this tragic disorder."
PSP affects up to 50,000 people in the United States at any given time. It is one-tenth as common as Parkinson's disease.
Also working on this study were neurologists Zbigniew Wszolek, M.D., and Ryan Uitti, M.D., from Mayo Clinic in Florida. The study's co-lead authors are at Philipps-Universität, Marburg, Germany; the University of Pittsburgh School of Medicine; the Children's Hospital of Philadelphia; Justus-Liebig-Universität in Giessen, Germany; and the University of Pennsylvania School of Medicine.
The study was funded by CurePSP/The Society for Progressive Supranuclear Palsy. The Mayo Clinic authors declare no conflicts of interest.
About Mayo Clinic Mayo Clinic is a nonprofit worldwide leader in medical care, research and education for people from all walks of life. For more information, visit www.mayoclinic.org/about/ and www.mayoclinic.org/news.
Kevin Punsky | EurekAlert!
Toward a 'smart' patch that automatically delivers insulin when needed
18.01.2017 | American Chemical Society
127 at one blow...
18.01.2017 | Stiftung Zoologisches Forschungsmuseum Alexander Koenig, Leibniz-Institut für Biodiversität der Tiere
Yersiniae cause severe intestinal infections. Studies using Yersinia pseudotuberculosis as a model organism aim to elucidate the infection mechanisms of these...
Researchers from the University of Hamburg in Germany, in collaboration with colleagues from the University of Aarhus in Denmark, have synthesized a new superconducting material by growing a few layers of an antiferromagnetic transition-metal chalcogenide on a bismuth-based topological insulator, both being non-superconducting materials.
While superconductivity and magnetism are generally believed to be mutually exclusive, surprisingly, in this new material, superconducting correlations...
Laser-driving of semimetals allows creating novel quasiparticle states within condensed matter systems and switching between different states on ultrafast time scales
Studying properties of fundamental particles in condensed matter systems is a promising approach to quantum field theory. Quasiparticles offer the opportunity...
Among the general public, solar thermal energy is currently associated with dark blue, rectangular collectors on building roofs. Technologies are needed for aesthetically high quality architecture which offer the architect more room for manoeuvre when it comes to low- and plus-energy buildings. With the “ArKol” project, researchers at Fraunhofer ISE together with partners are currently developing two façade collectors for solar thermal energy generation, which permit a high degree of design flexibility: a strip collector for opaque façade sections and a solar thermal blind for transparent sections. The current state of the two developments will be presented at the BAU 2017 trade fair.
As part of the “ArKol – development of architecturally highly integrated façade collectors with heat pipes” project, Fraunhofer ISE together with its partners...
At TU Wien, an alternative for resource intensive formwork for the construction of concrete domes was developed. It is now used in a test dome for the Austrian Federal Railways Infrastructure (ÖBB Infrastruktur).
Concrete shells are efficient structures, but not very resource efficient. The formwork for the construction of concrete domes alone requires a high amount of...
10.01.2017 | Event News
09.01.2017 | Event News
05.01.2017 | Event News
18.01.2017 | Power and Electrical Engineering
18.01.2017 | Materials Sciences
18.01.2017 | Life Sciences