Energy scarcity and impaired mitochondrial translation induce perinuclear stress granule clustering

Abstract

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 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. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=127 SRC="FIGDIR/small/578399v1_ufig1.gif" ALT="Figure 1"> View larger version (25K): org.highwire.dtl.DTLVardef@b32d48org.highwire.dtl.DTLVardef@161f848org.highwire.dtl.DTLVardef@f35c66org.highwire.dtl.DTLVardef@1375508_HPS_FORMAT_FIGEXP M_FIG C_FIG Inhibition of glycolysis and mitochondrial protein synthesis induces translocation of a swathe of ALS-FTD related proteins in primary human fibroblasts. The relocated proteins form concentric cytoplasmic rings (CCR) comprising stress granules, the Golgi and the aggresome, beside the nucleus. A perinuclear ring of stress granules forms in the mouse brain following intermittent nutrient restriction, with the glucose analog 2DG. The CCR is potentially a key intermediate step in the formation of pathological inclusions and so perturbed nutrient and energy metabolism encompassing impaired mitochondrial translation could precipitate the ALS-FTD disease cascade.