Brain variants of protein associated with Huntington's and other neurodegenerative diseases identified
The history of a Sicilian farmland estate is set in stone. Excavations show thousand years of existence.
(Medical Xpress) -- A protein essential for metabolism and recently associated with neurodegenerative diseases also occurs in several brain-specific forms. This discovery emerged in the course of a research project funded by the Austrian Science Fund FWF, the findings of which have now been published in the journal Human Molecular Genetics. The scientists working on the project discovered a large new region in the genetic code of the protein PGC-1alpha. Previously unknown variations of the protein, which can be found specifically in the brain, are produced from this region. This discovery may provide tissue-specific starting points for the development of new treatments for neurodegenerative diseases like Huntington's, Parkinson's and Alzheimer's.
PGC-1alpha is a real jack-of-all-trades. As a central regulator of metabolic genes that coordinate energy metabolism, the protein, which functions as a "transcriptional coactivator", influences major body functions. The extent to which the protein also influences medical conditions like obesity, diabetes and metabolic syndrome is unclear, and was under further investigation as part of a research project funded by the Austrian Science Fund FWF. In the course of their research, however, the scientists stumbled on unexpected findings with a particular relevance for neurodegenerative diseases.
A research team headed by Prof. Wolfgang Patsch from the Departments of Pharmacology and Toxicology, and Laboratory Medicine at the Paracelsus Medical University established that the gene which codes for PGC-1alpha (PPARGC1A) is six times larger than hitherto assumed. A new promoter was actually found at some distance (ca. 580 kb) from the previously known gene. A promoter is a DNA segment usually occurring upstream from a gene that can ultimately control how that gene is expressed as a protein. The transmission of genetic information from DNA to RNA molecules, i.e. transcription, is an important intermediate step in this process.
Transcripts, which are produced from the newly discovered promoter, were now examined in detail as part of the research project. "These transcripts differ in important regions from those encoded by the previously characterized - reference - PPARGC1A locus. Based on these differences, we were able to show that these previously unknown transcripts are produced specifically in human brain cells and are at least as common there as the reference transcripts," explains Dr. Selma M. Soyal, first author of the article currently published in Human Molecular Genetics. Further analyzes showed that the differences in the transcripts lead to the formation of proteins which differ from the protein that acts as a reference, in particular at the N-terminus. Other differences were found within the PGC-1alpha amino acid chain.
When the different PGC-1alpha proteins were localized in human cells (SH-SY5Y), another surprise awaited the scientists: whereas the reference protein was located mainly in the cell nucleus, one of the newly discovered variants was mainly found in the surrounding cytoplasm; another was found both in the nucleus and in the cytoplasm. According to Prof. Patsch: "It is likely that the differences we found in the transcripts influence mechanisms in the finished proteins which control their localization in the cell."
A Protein With Impact
The detailed functional characterization of the brain-specific proteins could prove significant, as PGC-1alpha is associated with various neurodegenerative diseases such as Huntington's disease, Parkinson's and Alzheimer's - a link that was also confirmed by the project. Using complex statistical analyses, sequence differences in the new promoter were examined in 1.706 Huntington patients as part of a collaboration with the European Huntington's Disease Network. A clear correlation emerged here between different sequence patterns and the age of onset of the disease in the patients. In addition, the scientists were also able to show that the newly discovered promoter is active in nerve tissue. This indicates that it may actually play an important role in the only partly known links between PGC-1alpha and the neurodegenerative diseases in question.
Overall, the findings of this project, which is funded by the Austrian Science Fund FWF, indicate complex functions of PGC-1alpha in humans. If the scientists succeed in reaching a better understanding of this complexity, PGC-1alpha could provide new possibilities for future therapeutic intervention in key neurodegenerative diseases.
More information: A greatly extended PPARGC1A genomic locus encodes several new brain-specific isoforms and influences Huntington disease age of onset. S. M. Soyal, et al. and For the European Huntington Disease Network. Human Molecular Genetics, 2012, doi: 10.1093/hmg/dds177
Journal reference: Human Molecular Genetics
Provided by Austrian Science Fund (FWF)
- Two proteins offer a 'clearer' way to treat Huntington's disease Jul 11, 2012 | not rated yet | 0
- Researchers explore PARIS; finds a key to Parkinson's Mar 03, 2011 | not rated yet | 0
- Metabolic disorder underlies Huntington's disease Oct 19, 2006 | not rated yet | 0
- Study explains how exercise helps patients with peripheral artery disease Dec 03, 2009 | not rated yet | 0
- In Parkinson's disease, brain cells abandon mitochondria Oct 06, 2010 | not rated yet | 0
- Motion perception revisited: High Phi effect challenges established motion perception assumptions Apr 23, 2013 | 3 / 5 (2) | 2
- Anything you can do I can do better: Neuromolecular foundations of the superiority illusion (Update) Apr 02, 2013 | 4.5 / 5 (11) | 5
- The visual system as economist: Neural resource allocation in visual adaptation Mar 30, 2013 | 5 / 5 (2) | 9
- Separate lives: Neuronal and organismal lifespans decoupled Mar 27, 2013 | 4.9 / 5 (8) | 0
- Sizing things up: The evolutionary neurobiology of scale invariance Feb 28, 2013 | 4.8 / 5 (10) | 14
Classical and Quantum Mechanics via Lie algebras
Apr 15, 2011 I'd like to open a discussion thread for version 2 of the draft of my book ''Classical and Quantum Mechanics via Lie algebras'', available online at http://lanl.arxiv.org/abs/0810.1019 , and for the...
- More from Physics Forums - Independent Research
More news stories
Researchers from Queen Mary, University of London have led the largest sequencing study of human disease to date, investigating the genetic basis of six autoimmune diseases.
Genetics May 22, 2013 | 4.5 / 5 (4) | 0 |
University of Minnesota Medical School researchers from the Masonic Cancer Center, University of Minnesota, in partnership with the University's Brain Tumor Program, have developed a new mouse model of malignant peripheral ...
Genetics May 20, 2013 | 5 / 5 (1) | 0 |
Northwestern University scientists have shown a gene involved in neurodegenerative disease also plays a critical role in the proper function of the circadian clock.
Genetics May 16, 2013 | 3 / 5 (1) | 1 |
Informed consent is the backbone of patient care. Genetic testing has long required patient consent and patients have had a "right not to know" the results. However, as 21st century medicine now begins to use the tools of ...
Genetics May 16, 2013 | 5 / 5 (1) | 3 |
Ethicists provide framework supporting new recommendations on reporting incidental findings in gene sequencing
In a paper published in Science Express, a group of experts led by bioethicists in the Center for Medical Ethics and Health Policy at Baylor College of Medicine provide a framework for the new American College of Medical Geneti ...
Genetics May 16, 2013 | not rated yet | 0
(Medical Xpress)—Regulating the distribution of power in neurons is done by a system that makes the national electric grid look simple by comparison. Each neuron has several thousand mitochondria confined ...
5 hours ago | 4.8 / 5 (5) | 0 |
Teams of highly respected Alzheimer's researchers failed to replicate what appeared to be breakthrough results for the treatment of this brain disease when they were published last year in the journal Science.
9 hours ago | 5 / 5 (1) | 2 |
A brief visual task can predict IQ, according to a new study. This surprisingly simple exercise measures the brain's unconscious ability to filter out visual movement. The study shows that individuals whose ...
11 hours ago | 4.9 / 5 (8) | 0 |
Scientists at the National Institutes of Health report they have discovered in mouse studies that a small molecule released in the spinal cord triggers a process that is later experienced in the brain as ...
9 hours ago | 5 / 5 (2) | 0 |
Little is known about why asthma develops, how it constricts the airway or why response to treatments varies between patients. Now, a team of researchers at Weill Cornell Medical College, Columbia University Medical Center ...
9 hours ago | not rated yet | 0 |
Ethnic background plays a surprisingly large role in how diabetes develops on a cellular level, according to two new studies led by researchers at the Stanford University School of Medicine.
7 hours ago | not rated yet | 0 |