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.
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.