 |
|
RNA Toxicity Contributes to Neurodegenerative Disease, University of Pennsylvania Scientists Say
May 22, 2008PHILADELPHIA -- Expanding on prior research performed at the University of Pennsylvania, Penn biologists have determined that faulty RNA, the blueprint that creates mutated, toxic proteins, contributes to a family of neurodegenerative disorders in humans.
Nancy Bonini, professor in the Department of Biology at Penn and an investigator of the Howard Hughes Medical Institute, and her team previously showed that the gene that codes for the ataxin-3 protein, responsible for the inherited neurodegenerative disorder Spinocerebellar ataxia type 3, or SCA3, can cause the disease in the model organism Drosophila. SCA3 is one of a class of human diseases known as polyglutamine repeat diseases, which includes Huntington's disease. Previous studies had suggested that the disease is caused largely by the toxic polyglutamine protein encoded by the gene.
The current study, which appears in the journal Nature, demonstrates that faulty RNA, the blueprint for the toxic polyglutamine protein, also assists in the onset and progression of disease in fruit fly models.
"The challenge for many researchers is coupling the power of a simple genetic model, in this case the fruit fly, to the enormous problem of human neurodegenerative disease," Bonini said. "By recreating in the fly various human diseases, we have found that, while the mutated protein is a toxic entity, toxicity is also going on at the RNA level to contribute to the disease."
To identify potential contributors to ataxin-3 pathogenesis, Bonini and her team performed a genetic screen with the fruit fly model of ataxin-3 to find genes that could change the toxicity. The study produced one new gene that dramatically enhanced neurodegeneration. Molecular analysis showed that the gene affected was muscleblind, a gene previously implicated as a modifier of toxicity in a different class of human disease due to a toxic RNA. These results suggested the possibility that RNA toxicity may also occur in the polyglutamine disease situation.
The findings indicated that an RNA containing a long CAG repeat, which encodes the polyglutamine stretch in the toxic polyglutamine protein, may contribute to neurodegeneration beyond being the blueprint for that protein. This raised the possibility that expression of the RNA alone may be damaging.
Long CAG repeat sequences can bind together to form hairpins, dangerous molecular shapes. The researchers therefore tested the role of the RNA by altering the CAG repeat sequence to be an interrupted CAACAG repeat that could no longer form a hairpin. Such an RNA strand, however, would still be a blueprint for an identical protein. The researchers found that this altered gene caused dramatically reduced neurodegeneration, indicating that altering the RNA structure mitigated toxicity. To further implicate the RNA in the disease progression, the researchers then expressed just a toxic RNA alone, one that was unable to code for a protein at all. This also caused neuronal degeneration. These findings revealed a toxic role for the RNA in polyglutamine disease, highlighting common components between different types of human triplet repeat expansion diseases. Such diseases include not only the polyglutamine diseases but also diseases like myotonic dystrophy and fragile X.
The family of diseases called polyglutamine repeat disorders arise when the genetic code of a CAG repeat for the amino acid glutamine stutters like a broken record within the gene, becoming very long. This leads to an RNA - the blueprint for the protein - with a similar long run of CAG. During protein synthesis, the long run of CAG repeats are translated into a long uninterrupted run of glutamine residues, forming what is known as a polyglutamine tract. The expanded polyglutamine tract causes the errant protein to fold improperly, leading to a glut of misfolded protein collecting in cells of the nervous system, much like what occurs in Alzheimer's and Parkinson's diseases.
Polyglutamine disorders are genetically inherited ataxias, neurodegenerative disorders marked by a gradual decay of muscle coordination, typically appearing in adulthood. They are progressive diseases, with a correlation between the number of CAG repeats within the gene, the severity of disease and age at onset.
In addition to Bonini, researchers whose work contributed to this study are Ling-Bo Li, formerly in the Department of Biology at Penn and now with the Department of Biochemistry at the University of Utah, and Zhenming Yu and Xiuyin Teng of the Department of Biology at Penn and the Howard Hughes Medical Institute.
Funding for this study was provided by the National Institute of Neurological Disorders and Stroke.
University of Pennsylvania
"The challenge for many researchers is coupling the power of a simple genetic model, in this case the fruit fly, to the enormous problem of human neurodegenerative disease," Bonini said. "By recreating in the fly various human diseases, we have found that, while the mutated protein is a toxic entity, toxicity is also going on at the RNA level to contribute to the disease."
To identify potential contributors to ataxin-3 pathogenesis, Bonini and her team performed a genetic screen with the fruit fly model of ataxin-3 to find genes that could change the toxicity. The study produced one new gene that dramatically enhanced neurodegeneration. Molecular analysis showed that the gene affected was muscleblind, a gene previously implicated as a modifier of toxicity in a different class of human disease due to a toxic RNA. These results suggested the possibility that RNA toxicity may also occur in the polyglutamine disease situation.
The findings indicated that an RNA containing a long CAG repeat, which encodes the polyglutamine stretch in the toxic polyglutamine protein, may contribute to neurodegeneration beyond being the blueprint for that protein. This raised the possibility that expression of the RNA alone may be damaging.
Long CAG repeat sequences can bind together to form hairpins, dangerous molecular shapes. The researchers therefore tested the role of the RNA by altering the CAG repeat sequence to be an interrupted CAACAG repeat that could no longer form a hairpin. Such an RNA strand, however, would still be a blueprint for an identical protein. The researchers found that this altered gene caused dramatically reduced neurodegeneration, indicating that altering the RNA structure mitigated toxicity. To further implicate the RNA in the disease progression, the researchers then expressed just a toxic RNA alone, one that was unable to code for a protein at all. This also caused neuronal degeneration. These findings revealed a toxic role for the RNA in polyglutamine disease, highlighting common components between different types of human triplet repeat expansion diseases. Such diseases include not only the polyglutamine diseases but also diseases like myotonic dystrophy and fragile X.
The family of diseases called polyglutamine repeat disorders arise when the genetic code of a CAG repeat for the amino acid glutamine stutters like a broken record within the gene, becoming very long. This leads to an RNA - the blueprint for the protein - with a similar long run of CAG. During protein synthesis, the long run of CAG repeats are translated into a long uninterrupted run of glutamine residues, forming what is known as a polyglutamine tract. The expanded polyglutamine tract causes the errant protein to fold improperly, leading to a glut of misfolded protein collecting in cells of the nervous system, much like what occurs in Alzheimer's and Parkinson's diseases.
Polyglutamine disorders are genetically inherited ataxias, neurodegenerative disorders marked by a gradual decay of muscle coordination, typically appearing in adulthood. They are progressive diseases, with a correlation between the number of CAG repeats within the gene, the severity of disease and age at onset.
In addition to Bonini, researchers whose work contributed to this study are Ling-Bo Li, formerly in the Department of Biology at Penn and now with the Department of Biochemistry at the University of Utah, and Zhenming Yu and Xiuyin Teng of the Department of Biology at Penn and the Howard Hughes Medical Institute.
Funding for this study was provided by the National Institute of Neurological Disorders and Stroke.
University of Pennsylvania
Polyglutamine News and Current Polyglutamine Events RSSA protein sequence associated with Huntington's disease may become life-saving vaccine component
On June 10, 2008 the scientific journal "Vaccine" published a paper by the Massachusetts based biotech company Cure Lab, Inc., demonstrating that a protein sequence important in neurodegenerative Huntington's disease can be safely used as a new generation of vaccine adjuvants.
Huntington's disease problem start early
The damaging effects of the mutated protein involved in Huntington's disease take place earlier in cell life than previously believed, said researchers from Baylor College of Medicine in Houston in a report that appears in the current edition of the journal Neuron.
Overexcited neurons not good for cell health
Neurotransmitters have consequences. They initiate events that are critical to a healthy life, giving us the ability to move, to talk, to breathe, to think. But that's if the neurotransmitters are getting it right and sending proper signals downstream to muscle cells, neurons or other cells.
Abnormal glutamine repeats interfere with key transcription factor, leading to neurodegeneration
Although repeating sequences of three nucleotides encoding some of the bodies' 20 amino acids are a normal part of protein composition, abnormal expansion of trinucleotide repeats is the known cause of multiple inherited neurodegenerative disorders, including Huntington disease.
Mechanism for neurodenegerative diseases linked to transport proteins
Hampering the transport of proteins within cells may underlie several adult-onset neurodegenerative diseases, such as Huntington's, ALS and Kennedy disease. Understanding how this cell transport is blocked in these diseases may offer targets for future therapy.
A clue to core problem of neurodegenerative disease and cell death
Misfolded and damaged proteins are common to all human neurodegenerative diseases. Clumps of these aggregated proteins destroy neurons within the brain and cause disease.
Study points to molecular origin of neurodegenerative disorders, including Huntington's disease
New research from the University of North Carolina at Chapel Hill School of Medicine points to the possible molecular origin of at least nine human diseases of nervous system degeneration.
More Polyglutamine News Articles
| PNAS April 27, 2004: Regulating Polyglutamine Aggregation (Proceedings of the National Academy of Sciences, v.101, # 17) by National Academy of Sciences pp.... | |
 | Human Nucleotide Expansion Disorders (Nucleic Acids and Molecular Biology) Human neurological and neuromuscular disorders caused by nucleotide expansion, first discovered in 1991, are the focus of growing interest of practicing physicians and of interested biomedical researchers. This volume represents a comprehensive and up-to-date description of many of the better-studied disorders. The expert authors discuss molecular, clinical and pathological aspects of the... |
| © 2008 BrightSurf.com |