亨廷顿病研究结果向毒性肽理论提出挑战
WESTPORT, CT (Reuters Health) - Researchers from the Mayo Clinic in Rochester, Minnesota have discovered that the mutant protein found in the brains of Huntington disease patients is resistant to proteolysis.
This finding challenges the widely held belief that accumulation of toxic peptides, which results from cleavage of the mutant protein, is the primary disease mechanism, according to a report published in the October 15th online edition of Nature Genetics.
Dr. Cynthia T. McMurray and Dr. Roy B. Dyer studied normal and mutant versions of the huntingtin protein (HD) and found that mutant HD was more resistant to proteolysis than was normal HD.
The peptide fragments that accumulate in affected brains arose from processing of normal HD, not mutant HD, the researcher report. However, mutant HD was found to sequester these fragments as well as complete normal HD. Therefore, mutant HD may promote disease by sequestering normal intracellular components and preventing them from performing their cellular functions.
"The current study arose from my interest in developing a treatment for Huntington disease," Dr. McMurray told Reuters Health. "I didn't want to start developing a therapy based on the toxic peptide theory if it was not accurate," she added.
"One of the problems I had with the toxic peptide theory is that it doesn't support the fact that Huntington disease is a late-onset disease," Dr. McMurray noted. "These mutant fragments are very toxic, so one would expect Huntington disease to occur much earlier in a patient's life."
Dr. McMurray noted that the toxic peptide theory was supported in many ways. "HD fragments were found in the brains of Huntington disease patients and expression of these fragments caused cells to die and mice to become sick," she added. However, there were problems with the studies that produced these findings.
In previous studies, "the fragments in patient's brains were detected using antibodies that could not distinguish mutant from normal fragments," Dr. McMurray noted. "Many studies proceeded to test the toxicity of mutant fragments, but they were flawed in that they assumed mutant fragments were generated in the first place," she explained.
Dr. McMurray believes "the current findings suggest that future investigations should focus on the whole mutant protein and not the fragments.", 百拇医药
This finding challenges the widely held belief that accumulation of toxic peptides, which results from cleavage of the mutant protein, is the primary disease mechanism, according to a report published in the October 15th online edition of Nature Genetics.
Dr. Cynthia T. McMurray and Dr. Roy B. Dyer studied normal and mutant versions of the huntingtin protein (HD) and found that mutant HD was more resistant to proteolysis than was normal HD.
The peptide fragments that accumulate in affected brains arose from processing of normal HD, not mutant HD, the researcher report. However, mutant HD was found to sequester these fragments as well as complete normal HD. Therefore, mutant HD may promote disease by sequestering normal intracellular components and preventing them from performing their cellular functions.
"The current study arose from my interest in developing a treatment for Huntington disease," Dr. McMurray told Reuters Health. "I didn't want to start developing a therapy based on the toxic peptide theory if it was not accurate," she added.
"One of the problems I had with the toxic peptide theory is that it doesn't support the fact that Huntington disease is a late-onset disease," Dr. McMurray noted. "These mutant fragments are very toxic, so one would expect Huntington disease to occur much earlier in a patient's life."
Dr. McMurray noted that the toxic peptide theory was supported in many ways. "HD fragments were found in the brains of Huntington disease patients and expression of these fragments caused cells to die and mice to become sick," she added. However, there were problems with the studies that produced these findings.
In previous studies, "the fragments in patient's brains were detected using antibodies that could not distinguish mutant from normal fragments," Dr. McMurray noted. "Many studies proceeded to test the toxicity of mutant fragments, but they were flawed in that they assumed mutant fragments were generated in the first place," she explained.
Dr. McMurray believes "the current findings suggest that future investigations should focus on the whole mutant protein and not the fragments.", 百拇医药