PARP-Inhibitors Reduce Damage in Some Neurological Disorders

They established that TDP-43 non-covalently bound to PAR via PAR-binding motifs embedded within its nuclear localization sequence. PAR binding promoted liquid-liquid phase separation of TDP-43 in vitro and was required for TDP-43 accumulation in stress granules in mammalian cells and neurons. Stress granule localization initially protected TDP-43 from disease-associated phosphorylation, but upon long-term stress, stress granules eventually dissolved, leaving behind aggregates of phosphorylated TDP-43.

The investigators reported in the August 9, 2018, online edition of the journal Molecular Cell that PARP inhibitors, which stop PAR from being generated, reduced the amount of harmful TDP-43 structures localized into stress granules. This reduced TDP-43-linked pathology and neurodegeneration and could be of use therapeutically for the treatment of ALS and FTD.

“Given the lack of treatment options, we are excited by these experiments that help elucidate molecular events that could lead to new therapeutics,” said senior author Dr. Nancy Bonini, professor of biology at the University of Pennsylvania.

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