RNA GRANULES, STRESS GRANULES AND PROCESSING BODIES:

M. GABRIELA THOMAS; M. ANDREA DESBATS;; JORGE CORREALE; GRACIELA L. BOCCACCIO

Los Cocos, Cordoba, Argentina

Congreso; VIII Taller Arentino de Neurociencias; 2006

RNA GRANULES, STRESS GRANULES AND PROCESSING BODIES: CYTOPLASMIC STRUCTURES INVOLVED IN mRNA REGULATION M. Gabriela Thomas, María Andrea Desbats, Jorge Correale and Graciela L. Boccaccio Instituto Leloir- IIBBA CONICET- FBMC, UBA. FLENI. Buenos Aires, Argentina. mthomas@leloir.org.ar In many neurodegenerative diseases cellular stress is one of the principal aspects that contributes to oligodendrocytes and neurons degeneration and death. There are several causes of stress, including inflammatory conditions and the presence of misfolded proteins. As in other cell types, oligodendrocytes stress response involves the inhibition of translation initiation as a consequence of eIF2a phosphorylation. We have recently reported that when exposed to stress conditions, the components of the translational machinery -usually located in the myelinating sheath- collapse in large perinuclear RNA-protein aggregates that were identified as stress granules (SGs) (Thomas et al., MBC 2005). SGs are transient structures thought to contain housekeeping mRNAs which are not translated during the stress response. Accordingly, we found that protein synthesis inhibition and eIF2a phosphorylation correlate temporally with SG formation. We observed that SMN (Survival of Motor Neuron) and FMRP (Fragil X-mental Retardation protein) –two RNA-binding proteins linked to neurodegenerative diseases- and the RNA binding protein Staufen form plastic ribonucleoparticles  that respond to the cellular translational state and can be converted into SGs upon different stressors. Thus SGs formation involves the remodeling of normal RNA granules as SGs include Poly(A)-binding protein (PABP), the RNA-binding proteins HuR and TIAR/TIA-1, and small but not large ribosomal subunits. In addition to SGs, eukaryotic cells contain another type of RNA granules called Processing Bodies (P bodies) or GW Bodies, constitutive cytosolic structures that participate in mRNA decay. We found that the P bodies components exoribonuclease Xrn1 and GW182 are recruited into SGs whereas the decapping enzyme Dcp1 is not. Growing SGs are frequently observed in close contact with P bodies. Our results suggest that a flux of mRNAs and proteins exists between RNA granules, translating polysomes, SGs and P bodies and that this is modulated to adapt to different environmental conditions, such as the oxidative stress and the ER-stress that occur during CNS diseases. Supported by NIH and Wadsworth Foundation (USA), and ANPCyT and FLENI (Argentina).