Claudia Colombrita (1), Valentina Gumina (1,2), Annamaria Maraschi (1), Alberto Doretti (1,2), Cinzia Tiloca (1), Vincenzo Silani (1,2), Antonia Ratti (1,2)
(1) Department of Neurology and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano, Milan, Italy
(2) Department of Pathophysiology and Transplantation, 'Dino Ferrari' Center - Università degli Studi di Milano, Milan, Italy
Abnormal cytoplasmic aggregates of TDP-43 protein represent a neuropathological hallmark of both familial and sporadic ALS and FTD diseases. TDP-43 is a mainly nuclear RNA-binding protein with multiple roles in RNA metabolism, including splicing, miRNA biogenesis, but also mRNA stability and transport. Our laboratory first demonstrated that in response to environmental insults TDP-43 is recruited into the cytoplasm within stress granules (SG), dynamic protein/RNA complexes which temporarily form to block translation. It has been recently suggested that in a condition of prolonged stress, as it occurs in the neurodegenerative process, SG would progressively fail to disassemble due to impaired autophagic/lysosomal activities and would turn into pathological TDP-43–containing inclusions. However, whether conditions of chronic stress induce the formation of SG has never been proven since they have been shown to form only upon short, sub-lethal stress exposure in vitro. We investigated this hypothesis by reproducing a status of chronic stress in primary fibroblasts and iPSC-derived motoneurons which were exposed to low doses of sodium arsenite for a prolonged timeframe. Formation of SG was observed in healthy control and ALS patients cells with differences in SG dynamics and protein components compared to acute stress SG. In mutant TARDBP and C9ORF72 cells, we also observed differences in SG number and size in a gene-specific manner. Our findings support the hypothesis that SG may represent the prelude to TDP-43 pathological aggregates in a condition of chronic and prolonged insult and may contribute to triggering neurodegeneration in ALS.
Keywords: stress granules, ALS, neurodegeneration, RNA-binding protein