Fernadez-Pelayo, U.; Munoz-Oreja, M.; Villar-Fernandez, M.; Lopez de Arbina, A.; Aiestaran- Zelaia, I.; Sanchez-Guisado, M. J.; Pantic, B.; Elicegui, A.; Zufiria, M.; Iruzubieta, P.; Sagartzazu-Aizpurua, M.; Aizpurua, J. M.; Gegg, M.; Alonso-Martin, S.; Ruiz-Cabello, J.; Gil Bea, F.; Spinazzola, A.; Lopez de Munain, A.; Holt, I.

Many proteins linked to amyotrophic lateral sclerosis and fronto-temporal dementia (ALS-FTD) change their cellular location and coalesce in cytoplasmic inclusion bodies in the disease state; yet the factors that govern protein relocation and organization remain unclear. Here, we show that inhibition of glycolysis and mitochondrial protein synthesis causes many proteins involved in ALS-FTD to change location, and form a novel structure comprising a ring of stress granules encircling the aggresome, a focal microtubule-based structure beside the nucleus. A perinuclear ring of stress granules also forms in activated microglia of mice exposed to the glycolytic inhibitor, 2-Deoxy-D-glucose. We propose that the new arrangement increases the risk of the stress granules merging and converting from the liquid phase to the insoluble inclusion characteristic of ALS-FTD. Thus, our findings suggest that compromised nutrient and energy metabolism can precipitate a molecular cascade that ultimately leads to the pathological hallmark of ALS-FTD the perinuclear inclusion body.