HspB8 enhances autophagic degradation of mutant misfolded proteins responsible for motorneuron diseases
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Data di Pubblicazione:
2011
Citazione:
HspB8 enhances autophagic degradation of mutant misfolded proteins responsible for motorneuron diseases / V. Crippa, P. Rusmini, E. Onesto, D. Sau, E. Giorgetti, S. Gaureschi, M. Galbiati, M. Marino, C. Bendotti, S. De Biasi, A. Poletti, S. Guareschi. ((Intervento presentato al 16. convegno TELETHON CONVENTION tenutosi a Riva del Garda nel 2011.
Abstract:
Motorneuron diseases (MNDs) comprise different types of neurodegenerative diseases in which upper and/or lower motorneurons are affected. While some MNDs forms are linked to gene mutations causing loss-of-functions of proteins essential for motorneuronal survival, several others MNDs are caused by an aberrant behavior of proteins that become toxic to motorneurons. In the latter case, the neurotoxic event often derives from aberrant conformations (misfolding) consequent to gene mutations or other mechanisms, which might trigger and perturb a wide variety of processes affecting motor neuron functions and survival. SpinoBulbar Muscular Atrophy (SBMA or Kennedy's disease) and some forms of Amyotrophic Lateral Sclerosis (ALS) are examples of this type of MNDs, since they have been linked to neurotoxic gain-of-function(s) of specific proteins. SBMA is linked to a mutant androgen receptor (AR) containing an elongated polyglutamine tract (ARpolyQ). Several familial ALS (fALS) are linked to point mutations in Superoxide Dismutase 1 (SOD1) or in the TDP-43 genes. Notably, the TDP-43 gene encodes a protein involved also in most sporadic ALS (sALS). The proteins AR, SOD1 and TDP-43 are totally unrelated and do not share structural or functional domains but, when mutated, are thought to misfold and to alter similar pathways in motor neurons. In transgenic (tg) G93A-SOD1 mice, widely used as fALS animal model, we observed an accumulation of insoluble SOD1 which was partially linked to an inhibition of proteasome. we also observed several autophago-lysosomal structures in affected surviving lumbar spinal cord motorneurons indicating autophagy activation. Interestingly, we found that, at the end stage of disease, the surviving spinal cord motorneurons accumulating mutant SOD1, also over-expressed very high levels of a small heat shock proteins B8 (HspB8).
Using motor neuronal cell models of SBMA and fALS, we already found that mutant ARpolyQ and SOD1, as well as a truncated form of TDP-43 showed alteration in their solubility and clearance, accumulating into aggregates that impaired the proteasome functions impacting on the autophagic process. We then found that HspB8 decreases aggregation and increases solubility and clearance of mutant ARpolyQ, SOD1 and frTDP-43, without affecting the turnover of the wild type proteins. Notably, HspB8 acts on these misfolded proteins even when the proteasome activity is specifically blocked, and is paralleled by the formation of LC3-II-positive autophagosomes. On the other hand, autophagy blockage resulted in a dramatic increase of ARpolyQ, mutant SOD1 or frTDP-43 aggregates. The effects of HspB8 seem to be mediated by autophagy, since autophagic flux blockage resulted in the accumulation of mutant SOD1 into the HspB8/Bag3/Hsc70/CHIP multi-heteromeric complex. This complex is known to selectively activate the p62-mediated autophagic removal of misfolded proteins in muscle cells. Thus, we postulate that HspB8 increases mutant misfolded protein clearance via autophagy in motorneurons.
Interestingly, in fALS muscle cell models, we did not found mutant SOD1 aggregates or proteasome alteration, but an intense activation of autophagy. Moreover, in muscle tissue of tg G93A-SOD1 mice the over-expression of HspB8 was about ten times more intense than in wt mice, suggesting an important role of autophagy in the removal of misfolded proteins in muscle cells.
Collectively, these results demonstrate that by assisting misfolded proteins processing with selected intracellular chaperones, it is possible to affect their clearance and to decrease their aggregation by stimulating autophagy without impairing the functions of the intracellular degradative systems.
Tipologia IRIS:
14 - Intervento a convegno non pubblicato
Elenco autori:
V. Crippa, P. Rusmini, E. Onesto, D. Sau, E. Giorgetti, S. Gaureschi, M. Galbiati, M. Marino, C. Bendotti, S. De Biasi, A. Poletti, S. Guareschi
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