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Mechanism related to the onset of various genetic diseases revealed
September 18, 2009UAB researchers discover that the separation of 2 or more proteins due to genetic mutations causes them to malfunction
Researchers at the Department of Biochemistry and Molecular Biology of Universitat Autònoma de Barcelona (UAB) have revealed the process by which proteins with a tendency to cause conformational diseases such as amyotrophic lateral sclerosis, familial amyloidotic polyneuropathy, familial amyloidotic cardiomyopathy, etc. finally end up causing them. Researchers have carried out an analysis of their 3D structure and studied why these proteins finally become toxic although they are correctly folded, an indicator that they are functioning correctly. The answer can be found in the separation of the proteins, which under normal conditions are found in groups of two or more, caused by a genetic mutation in their composition. Researchers believe this discovery, published recently in the journal PLoS Computational Biology, could also be the cause of other diseases of unknown origins.
Every day cells produce thousands of new proteins which renew themselves every second and which, by obeying the orders prescribed in our genetic code, work towards the proper functioning of our body. However, these proteins occasionally suffer genetic mutations which can cause changes in their composition, thus preventing them from carrying out their functions and the activities they are assigned. In many cases this gives way to the formation of toxic macromolecular aggregates - amyloid fibrils - which block our body's protein quality control system and finally provoke cell death.
Protein aggregation and the misfolding of proteins can be linked to the origin of many conformational diseases which can be either genetic or spontaneous. The proteins involved can either have an unstructured or lineal unfolded form such as in Alzheimer's and Parkinson's disease or Type II Diabetes, or can be globular, showing a folded 3D-structure. The former have been widely characterised by scientists and the process by which they unfold is known. The process leaves regions uncovered which are in the risk of becoming aggregated and these eventually form toxic assemblies. Globular proteins are known to be linked to hepatic, cardiac, renal and neurological disorders. However scientists do not know exactly how they manage to aggregate despite the fact that they are correctly folded within the body.
Through computational analysis, researchers Salvador Ventura and Virgínia Castillo, from the UAB Department of Biochemistry and Molecular Biology, have discovered that, in non-disease conditions, globular proteins related to conformational diseases are found associated in pairs to other proteins or in complex subunits, in a way that one protein covers the aggregation-prone region of the other and thus prevents the onset of this process. Therefore these regions remain obscured in the interior of the structure and are inoffensive to the organism as long as the two proteins are joined together. Researchers have found that genetic mutations produced in the interaction sites of the protein pair prevents their association, leaving aggregation-prone regions uncovered and favouring the formation of toxic aggregates. According to researchers, this would explain why out of two people with the same globular proteins and the same risk regions, only the one who suffers a genetic mutation would finally develop a disease.
The conclusions obtained have led researchers to contemplate the possibility that dissociation is a general mechanism, which not only affects globular proteins with a clearly defined structure, but also others which have not yet been characterised and which could be the cause of diseases of unknown origin.
As possible strategies to prevent the dissociation of proteins, the authors propose introducing genetic mutations into the proteins to strengthen their association and developing specific molecules to block the risk regions of already dissociated proteins.
The results of the study carried out by UAB researchers coincides with those obtained by researchers at Cambridge University, who also published similar data in the journal Proceedings of the National Academic of Sciences.
In the future UAB researchers are planning to expand their computational analysis to cover the whole set of human proteins with a defined 3D-structure. With this objective they seek to discover the proteins responsible for different genetic diseases of unknown origins and offer a series of new therapeutic targets for these disorders.
Universitat Autonoma de Barcelona
Protein aggregation and the misfolding of proteins can be linked to the origin of many conformational diseases which can be either genetic or spontaneous. The proteins involved can either have an unstructured or lineal unfolded form such as in Alzheimer's and Parkinson's disease or Type II Diabetes, or can be globular, showing a folded 3D-structure. The former have been widely characterised by scientists and the process by which they unfold is known. The process leaves regions uncovered which are in the risk of becoming aggregated and these eventually form toxic assemblies. Globular proteins are known to be linked to hepatic, cardiac, renal and neurological disorders. However scientists do not know exactly how they manage to aggregate despite the fact that they are correctly folded within the body.
Through computational analysis, researchers Salvador Ventura and Virgínia Castillo, from the UAB Department of Biochemistry and Molecular Biology, have discovered that, in non-disease conditions, globular proteins related to conformational diseases are found associated in pairs to other proteins or in complex subunits, in a way that one protein covers the aggregation-prone region of the other and thus prevents the onset of this process. Therefore these regions remain obscured in the interior of the structure and are inoffensive to the organism as long as the two proteins are joined together. Researchers have found that genetic mutations produced in the interaction sites of the protein pair prevents their association, leaving aggregation-prone regions uncovered and favouring the formation of toxic aggregates. According to researchers, this would explain why out of two people with the same globular proteins and the same risk regions, only the one who suffers a genetic mutation would finally develop a disease.
The conclusions obtained have led researchers to contemplate the possibility that dissociation is a general mechanism, which not only affects globular proteins with a clearly defined structure, but also others which have not yet been characterised and which could be the cause of diseases of unknown origin.
As possible strategies to prevent the dissociation of proteins, the authors propose introducing genetic mutations into the proteins to strengthen their association and developing specific molecules to block the risk regions of already dissociated proteins.
The results of the study carried out by UAB researchers coincides with those obtained by researchers at Cambridge University, who also published similar data in the journal Proceedings of the National Academic of Sciences.
In the future UAB researchers are planning to expand their computational analysis to cover the whole set of human proteins with a defined 3D-structure. With this objective they seek to discover the proteins responsible for different genetic diseases of unknown origins and offer a series of new therapeutic targets for these disorders.
Universitat Autonoma de Barcelona
Genetic Disease Current Events and Genetic Disease News RSS1930s drug slows tumor growth
Drugs sometimes have beneficial side effects. A glaucoma treatment causes luscious eyelashes. A blood pressure drug also aids those with a rare genetic disease.
1 shot of gene therapy and children with congenital blindness can now see
Born with a retinal disease that made him legally blind, and would eventually leave him totally sightless, the nine-year-old boy used to sit in the back of the classroom, relying on the large print on an electronic screen and assisted by teacher aides.
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Skin cells may provide early warning for cancer risk elsewhere in body
While some scientists have argued that cancer is such a complex genetic disease that you'd have to sequence a person's complete genome in order to predict his or her cancer risk, a University of California, Berkeley, cell biologist suggests that the risk may be more simply determined by inexpensively culturing a few skin cells.
Study of huge numbers of genetic mutations point to oxidative stress as underlying cause
A study that tracked genetic mutations through the human equivalent of about 5,000 years has demonstrated for the first time that oxidative DNA damage is a primary cause of the process of mutation - the fuel for evolution but also a leading cause of aging, cancer and other diseases.
Mutation responsible for cystic fibrosis also involved in muscle atrophy
Patients with cystic fibrosis (CF) usually experience significant muscle loss, a symptom traditionally considered to be a secondary complication of the devastating genetic disease.
July 23, 2009 Circulating osteogenic precursor (COP) cells form bone in vivo. Bone from Blood: Circulating Cells Form Bone Outside the Normal Skeleton, Penn Study Finds
The accepted dogma has been that bone-forming cells, derived from the body's connective tissue, are the only cells able to form the skeleton.
Preimplantation genetic diagnosis may pose neurological risks
Preimplantation genetic diagnosis (PGD) has helped many couples conceive healthy children and is generally considered a safe practice.
New test can detect both genetic and chromosomal abnormalities in embryos
One-step screening for both genetic and chromosomal abnormalities has come a stage closer as scientists announced that an embryo test they have been developing has successfully screened cells taken from spare embryos that were known to have cystic fibrosis.
Women with cystic fibrosis can have safe and successful fertility treatment
Women with cystic fibrosis can have fertility treatment to help them have babies without any long-term adverse effects on either themselves or their children.
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