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PARP inhibitors show promise for treating and preventing brain disorders

PARP inhibitors show promise for treating and preventing brain disorders

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A class of cancer drugs called PARP inhibitors could be useful for treating and preventing brain disorders, including amyotrophic lateral sclerosis (ALS), also called Lou Gehrig’s disease, and some forms of frontotemporal degeneration (FTD), by halting the misplacement of specific proteins that affect nerve cells, according to a study published in Molecular Cell by researchers in the the School of Arts and Sciences and the Perelman School of Medicine at the University of Pennsylvania.

The protein TDP-43, when mistakenly outside the nucleus, forms clumps in brain cells that are affected in ALS and FTD. When out-of-place TDP-43 binds to another molecule, PAR, it amasses in cellular structures called stress granules. While this initial accumulation does not cause imminent harm to a cell, after a prolonged period, TDP-43 changes into structures that are observed in brain diseases. Now, a team led by Nancy Bonini, PhD, a professor of Biology, and James Shorter, PhD, a professor of Biochemistry and Biophysics, have found that PARP inhibitors, which stop PAR from being generated, reduced the amount of harmful TDP-43 structures in cells under stress.

In test-tube experiments, the team found that TDP-43 can change from a soluble form to a condensed liquid form by interacting with other TDP-43 molecules and macromolecules like PAR. “The liquid form of TDP-43 is representive of a stress granule and is likely beneficial,” Shorter said; however, he noted that if these liquid forms of TDP-43 solidify with time they can be difficult to remove.

While this work is still being done in the lab, the team’s findings provide the next step for neurologists looking for new ways to fight neurodegenerative disorders. “Given the lack of treatment options, we are excited by these experiments that help elucidate molecular events that could lead to new therapeutics,” said Bonini.

Source:

https://www.pennmedicine.org/news/news-releases/2018/august/drugs-in-development-for-cancer-may-also-fight-brain-diseases-including-als

Posted in: Medical Science News | Medical Research News | Medical Condition News | Pharmaceutical News

Tags: Biochemistry, Brain, Cancer, Cell, Drugs, Education, Healthcare, Hospice, Hospital, Lou Gehrig’s Disease, Macromolecules, Medical School, Molecule, Nerve, Nucleus, Protein, Research, Sclerosis, Stress, TDP-43, therapeutics

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