RNAGranules, Stress Granules and Processing Bodies: Cytoplasmic Structures Involved in mRNA

THOMAS MG; DESBATS MA; CORREALE J; BOCCACCIO GL

Huerta Grande, Córdoba, Argentina

Taller; Taller de Neurociencias; 2006

Taller de Neurociencias

In many neurodegenerative diseases cel!ular stress is cne of the principal aspects tha! contributes to oligodendrocytes and neurons degeneration and death. There are several causes of stress, including inflammatory conditions and the presence of misfoJded proteins. As in other cel! types, oligodendrocytes stress response in vol ves the inhibition of translation initiation as a consequence of elF2a phosphorylation. We have recently reported !hat when exposed to stress conditions, the components of the translational machinery -usuaUy located in the myeHnating sheath- col!apse 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 transJated during the stress response. Accordingly, we found that protein synthesis inhibitionand elF2a phosphorylation correlate temporal!y 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 ribonudeoparticles 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 inelude Poly(A}-binding protein (PABP), the RNA-bínding proteios HuR and TIARfTIA-1, and sma!! but not largeribosomal subunits. In addition to SGs, eukaryotic cells contain another type of RNA granuJes called Processing Bodíes (P.bodies) or GW Sodies, 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 clase 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 ERstress that occur during CNS diseases.