The protein quality control system in motoneuron diseases.

6th March 2015

Versione stampabile

Venue: Edificio Povo 1, via Sommarive nr. 5, Povo (Tn) - Room A207
 at 10:00 a.m.

  • Angelo Poletti -  Dipartimento di Scienze Farmacologiche e Biomolecolari Universita’ degli Studi di Milano

Motor neuron diseases, like spinobulbar muscular atrophy (SBMA) and amyotrophic lateral sclerosis (ALS) are characterized by the presence of inclusions o aggregates of proteinaceous materials. In SBMA, aggregates contain mutant androgen receptors (AR) with an elongated polyglutamine tract (ARpolyQ), responsible for disease, while in ALS aggregates contain TDP43, ubiquilin, optineurin, etc. Exceptions are familial ALS forms linked to superoxide dismutase 1 (SOD1) mutations, in which aggregates are composed of mutant SOD1. In general, protein aggregation is due to generation of aberrant protein conformations (misfolding). Thus, in neuronal cells, the protein quality control (PQC) system may be insufficient to correctly remove the misfolded proteins. The PQC system requires the activities of efficient chaperones and of the degradative systems ubiquitin-proteasome (UPS) and autophagy. After misfolded protein recognition by chaperones, the dynein motor complex plays a crucial role to efficiently remove these species via autophagy transporting them to autophagosome and assisting autophagosome-lysosome fusion. We found that motoneurons may responds to misfolded species by activating the expression of a small HSP, HSPB8, which facilatate the autophagic removal of misfolded species, restoring a proper autophagic flux. The HSPB8 acts in conjunction with a co-chaperone BA3, which is delivered by dynein in a complex with HSC70-CHIP to the microtubules organization center where autophagosomes are assembled. Here, CHIP ubiquitinated misfolded protein substrates allowing their recognition by p62 and clearance from the motoneurons. Thus, together, the PQC and the HSPB8 proteins help to protect motoneurons from damages associated to the presence of aberrant protein species accumulating in affected cells.