Degrees of stress in neurodegeneration

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Science  31 Aug 2018:
Vol. 361, Issue 6405, pp. 889-890
DOI: 10.1126/science.361.6405.889-b

In the neurodegenerative disorder amyotrophic lateral sclerosis (ALS), the nuclear protein called transactive response DNA binding protein of 43 kDa (TDP-43) accumulates in stress granules within the cytoplasm of neurons and glia and is linked to disease pathology. McGurk et al. report that TDP-43 binds to poly(ADP-ribose) (PAR), which triggers phase separation of TDP-43 and its subsequent recruitment to stress granules. Under short-term stress, phosphorylated TDP-43, which is considered a hallmark of disease, is unexpectedly excluded from stress granules. This finding indicates that the granules initially prevent phosphorylated TDP-43 aggregation unless stress is prolonged. This work also points to an approach to ALS treatment by inhibition of PAR polymerase (PARP) to reduce PAR production. For instance, a small-molecule inhibitor of PARP that prevents cancer-cell proliferation also blocks cytoplasmic TDP-43 aggregation.

Mol. Cell 10.1016/j.molcel.2018.07.002 (2018).

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