The 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.

The autophagosome and lysosome pathway in motoneuron diseases / A. Poletti. - In: JOURNAL OF NEUROCHEMISTRY. - ISSN 0022-3042. - 142:suppl. 1(2017 Aug 24), pp. 47-47. ((Intervento presentato al convegno ISN-ESN tenutosi a Paris nel 2017.

The autophagosome and lysosome pathway in motoneuron diseases

A. Poletti
Primo
2017

Abstract

The 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.
HSPB8; autophagy; proteasome; chaperones; SBMA; ALS; motoneuron diseases; neutrons; cell death
Settore BIO/13 - Biologia Applicata
24-ago-2017
International Society for Neurochemistry
European Society for Neurochemistry
https://www.neurochemistry.org/biennial-meeting/scientific-information/submit-your-abstract.html
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/521730
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