Unexpected Treatment Options for Debilitating Neurodegenerative Disorders


An emerging class of cancer drugs may help treat brain disorders such as amyotrophic lateral sclerosis frontotemporal dementia.

amyotrophic lateral sclerosis, dementia

Results from a new study suggest that an emerging class of cancer drugs called PARP inhibitors may also have therapeutic value in treating brain disorders like amyotrophic lateral sclerosis (ALS) frontotemporal dementia (FTD).1

The study found that these drugs may stop abnormal clumping of a toxic protein called TDP-43, a hallmark in the pathophysiology of these debilitating neurodegenerative disorders. TDP-43 is an RNA binding protein that forms clumps in the brain of almost all individuals with ALS, and about 50% of people with FTD.

“What excited me about pursuing this pathway was the promise of small molecules that attack the disease process of TDP-43,” first author Leeanne McGurk, PhD, a research associate at the University of Pennsylvania (Philadelphia, PA), said in a press release.

“When I tested them on cultured cells, I found they could alleviate the buildup of TDP-43 that mirrors the abnormal protein clumps we see in disease,” she added.

Two PARP inhibitors, Lynparza (Astrazeneca) and Zejula (Tesaro), are already being used to treat breast or ovarian cancer with BRCA mutations.

In the study, researchers conducted laboratory experiments in Drosophila flies, mammalian cells, and brain and spinal cord tissue from people with ALS.

A key concept in these experiments is the idea of cytoplasmic stress granules, which have been implicated in the pathogenesis of ALS and FTD. TDP-43 is normally found inside the nucleus, but it can sometimes get out of place.  When outside the nucleus, TDP-43 binds a molecule called PAR, which can regulate the formation of stress granules. TDP-43 binding to PAR causes it to accumulate in stress granules and stimulates it to separate into liquid form.

“The liquid form of TDP-43 is representative of a stress granule and is likely beneficial,” co-lead author James Shorter, PhD, said in the press release.

Over the short-term, the stress granule protects TDP-43 from chemical changes that lead to clumping. But over the long-term, the granules dissolve and TDP-43 solidifies, leaving clumps behind in the brains of individuals with ALS and FTD.

The study showed that a specific PARP called tankyrase regulates the accumulation of TDP-43 in the cytoplasm. Inhibiting tankyrase can interfere with the generation of PAR, and in turn decrease the amount of stress granules that harbor TDP-43 in the cytoplasm. Experiments suggested that doing so may prevent neurodegeneration.

“The PARP inhibitors we tested that antagonized the cytoplasmic accumulation of TDP-43 may one day be optimized as valuable therapeutics for brain diseases,” coauthor Edward Gomes, MS, said in the press release.

While more work needs to be done before these results can be applied to humans, the study may provide an important first step in finding new treatments for these devastating brain diseases.

“Given the lack of treatment options, we are excited by these experiments that help elucidate molecular events that could lead to new therapeutics,” co-lead author Nancy Bonini, PhD, added in the press release.

Take Home Points

• Laboratory experiments suggest that an emerging class of cancer drugs called PARP inhibitors may help treat ALS and FTD

• The hallmark TDP-43 protein forms clumps in the brain of almost all individuals with ALS, and about 50% of people with FTD.

• Experiments suggested that PARP inhibitors can decrease clumping of TDP-43, which may prevent neurodegeneration


1. McGurk L, Gomes E, Guo L, et al. Poly(ADP-Ribose) Prevents Pathological Phase Separation of TDP-43 by Promoting Liquid Demixing and Stress Granule Localization. Mol Cell. 2018;71:703-717.

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