Here we propose three plausible pathways by which changes in cellular or whole-body metabolism may lead to protein aggregation in ALS and FTLD (Fig. 1).Physiological stress granules have been proposed to act as precursors of abnormal TDP-43 and FUS inclusions in ALS/FTLD [135], supported by the observation that stress granule components co-aggregate with TDP-43 and FUS [14]. Here, FUS is linked to amyotrophic lateral sclerosis.