A study led by St. Jude Children's Research Hospital investigators links the muscle weakness and other symptoms of a rare neurodegenerative disease to a misstep in functioning of a normal protein, rather than its build-up inside cells. The finding offers insight into the mechanism driving common nervous system disorders like Parkinson's and Alzheimer's diseases.
The work advances understanding of how the inherited mistake at the heart of spinobulbar muscular atrophy (SBMA) leads to the death of neurons in the brain and spinal cord. Investigators showed that the underlying mutation caused an amplification of the protein's normal function. The work appears in the September 23 online edition of the scientific journal Neuron.
"The idea that toxicity is mediated by the native, or normal, function of the protein itself is a departure from conventional wisdom. This research adds to growing evidence the principle applies very broadly in other neurodegenerative disorders, including Alzheimer's and Parkinson's diseases," said J. Paul Taylor, M.D., Ph.D., an associate member in the St. Jude Department of Developmental Neurobiology and the paper's senior author.
The current neurodegenerative disease model links the disorders to a toxic build-up of improperly folded proteins inside cells. Taylor said: "Our findings suggest the focus on protein aggregation inside cells may be misplaced." Developing therapies that target the normal protein function will likely be easier and more effective, he added.
Medications are already available to block the androgen receptor (AR) protein, which is mutated in SBMA. Work is now underway in Taylor's laboratory to identify drugs that more selectively block AR functioning.
SBMA belongs to a family of eight disorders, including Huntington's disease, which stem from an overabundance of the same small, repeated sequence of DNA known as a trinucleotide. Such repetitions are common throughout t
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St. Jude Children's Research Hospital