Scientists at the Case Western Reserve University School of Medicine have determined the structure of protein fibrils linked to Lou Gehrig's disease and other neurodegenerative disorders. Their findings were published in Nature Communications.
"These devastating brain disorders that affect tens of thousands of Americans are on the rise worldwide, and there are no effective treatments to stop their progression," said Witold Surewicz, senior author.
By using cryo-electron microscopy, the authors analyzed thousands of images of fibrils formed in the test tube by the key fragment of TDP-43. They determined the complex architecture of these elongated structures at a resolution close to individual atoms. This structural insight revealed, among other findings, the nature of the template on which more copies of TDP-43 can lock.
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Based on this structural model, the researchers also discussed how the fibril structure could be controlled by amino acid mutations in TDP-43 linked to hereditary forms of ALS and FTD, as well as by aging-dependent modifications of the protein. "Detailed knowledge about fibrillar structures formed by TDP-43 may also lead to the development of drugs to treat these devastating brain disorders," Surewicz concluded.