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Jan 26

Packard researchers identify key component of stress granules and ALS pathology

ALS Headlines, Packard Center News
Udai Pandey is a researcher at the University of Pittsburgh Medical Center

With the help of a recently identified protein, a team of researchers led by Packard scientist Udai Pandey at the University of Pittsburgh Medical Center and including Packard science director Piera Pasinelli at Thomas Jefferson University has linked several different types of molecular pathology commonly found in ALS patients.

The protein, known as Pur-alpha, binds to DNA and RNA and was recently shown to bind to the C9orf72 repeat expansion, the most common genetic cause of ALS. Since other RNA binding proteins, such as TDP-43, FUS, Matrin-3, and VCP have also been linked to ALS, scientists had hypothesized that alterations to RNA metabolism might underlie the molecular changes that lead to motor neuron degeneration. These RNA-binding proteins have also been linked to the formation of stress granules in the cytoplasm. As their name indicates, stress granules form when the cell is stressed. However, in ALS patients, they don’t dissolve after the stressful event has passed, and many important cellular proteins remain sequestered and unable to do their jobs. A major line of research in the ALS community has been working to understand the factors that cause these stress granules to form and dissolve.

In the new study in Acta Neuropathologica, Pandey, Pasinelli, and colleagues studied the role of Pur-alpha in FUS-related neurodegeneration. Using cells from ALS patients carrying FUS mutations, as well as age/sex-matched controls, mammalian neuronal cells (N2a) and mammalian primary motor neurons, the researchers showed that Pur-alpha is a key component of stress granules and becomes trapped in these in ALS patient cells. Reducing the amount of Pur-alpha made by the cell also lowers the cell’s ability to form stress granules under stressful conditions, indicating that Pur-alpha is a key component of stress granules. Further experiments revealed that FUS and Pur-alpha physically interact, and that these interactions aren’t affected by FUS mutations.

Previous work by the Pandey lab had shown that normally, FUS is found in the cell’s nucleus. However, in ALS-linked FUS mutations, the protein is found predominantly in the cytoplasm instead of the nucleus. The expression of Pur-alpha restored nuclear localization in roughly 80 percent of primary motor neurons, and it also helped reduce the cellular toxicity associated with mutant FUS in primary motor neurons. Importantly, ectopic expression of Pur-alpha promoted turnover of FUS-positive stress granules. 

Together, the results indicate a possible molecular pathway underlying ALS. Mutations in RNA-binding proteins lead to the formation of stress granules that don’t dissolve, causing FUS and Pur-alpha to get stuck in these granules. This triggers a chain reaction of toxic events that ultimately leads to the motor neuron degeneration and death seen in ALS. The expression of Pur-alpha helps reduce this toxicity, suggesting new potential therapeutic targets.

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