Characterization of a novel cytoplasmic superstructure induced by inhibition of glycolysis and mitochondrial protein synthesis (and its implications for ALS-FTD)

Stress granules and the aggresome are structures that form in response to disrupted protein
homeostasis. The former include TARDBP binding protein 43 (TDP-43) and other RNA binding
proteins that ordinarily reside in the nucleus, whereas the aggresome is a microtubule based
structure that gathers ubiquitinated proteins. Both attract scientific and medical, as well as
scientific interest because of their potential to provide insights into the cytoplasmic inclusion
bodies that form in the neurodegenerative diseases amyotrophic lateral sclerosis and fronto-
temporal dementia (ALS-FTD), and that contain TDP-4-P and ubiquitinated protein. Here, in this thesis I show that inhibition of glycolysis and mitochondrial protein synthesis induces the formation of a novel cellular superstructure comprising a ring of stress granules encircling the aggresome. A perinuclear ring of stress granules also forms in activated microglia of mice exposed to the glycolytic inhibitor, 2-Deoxy-D-glucose. The location of the stress granule ring beside the nucleus coincides with that of the ALS-FTD inclusion body; thus, the ring may represent an intermediate stage in the formation of the perinuclear inclusion that is the pathological hallmark of ALS-FTD.