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The autophagosome and lysosome pathway in motoneuron diseases
No full textThe intracellular organelles autophagosomes and lysosomes are the essential components of a high capacity degradative pathway. Autophagosomes have two double layer membranes and are formed by engulfing damaged, misfolded and aggregated proteins or even organelles to be cleared from cells. Autophagosomes fuse with lysosomes, and the entire content of the newly formed autophago-lysosomes is digested by the lysosomal enzymes. The entire process is named autophagy, an essenzial component of the protein quality control (PQC) system in cells. The PQC system also requires chaperones and the proteasome that work synergistically to autophagy degradative pathways.
Autophagy is altered in motorneuronal diseases (MNDs), like Spinal bulbar muscular atrophy (SBMA) and Amyotrophic lateral sclerosis, in which specific mutant or aberrant misfolded proteins accumulate causing autophagic flux blockage, possibly leading to neuronal death.
We found that a peculiar chaperone, the small heat shock protein (HSP) B8, is able to revert the autophagy flux blockage by facilitating the autophagic removal of misfolded proteins prone to aggregate in MNDs. HSPB8 is induced in response to several neuronal stresses such has proteotoxic and oxidative stresses. We found that HSPB8 is highly induced in the two main targets of misfolded protein toxicity in tg mice models of SBMA and ALS, the motorneurons and the muscle. HSPB8 acts in conjunction with BAG3 to bind the HSC70-CHIP mediator of degradation, and the pharmacological or genetic induction of HSPB8 expression is protective in MNDs, while its silencing has opposite effects. We also showed that HSPB8 protects from a misfolded protein induced aberrant phenotype in fly models of ALS.
By increasing the HSPB8-mediated selective targeting of misfolded proteins to autophagy neurons and muscle reduce their proteasome-mediated clearance limiting its possible overwhelming.
Therefore, pharmacological approached which potentiate the HSPB8-BAG3 autophagic pathway could contribute to maintain a correct proteostasis in motorneuron and muscle cells and might have therapeutic implication in MNDs
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