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!
Water forms 'spine of hydration' around DNA, group finds
26.05.2017 | Cornell University
How herpesviruses win the footrace against the immune system
26.05.2017 | Helmholtz-Zentrum für Infektionsforschung
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...
An Australian-Chinese research team has created the world's thinnest hologram, paving the way towards the integration of 3D holography into everyday...
24.05.2017 | Event News
23.05.2017 | Event News
22.05.2017 | Event News
26.05.2017 | Life Sciences
26.05.2017 | Life Sciences
26.05.2017 | Physics and Astronomy