The Role of the Heat Shock Protein B8 (HSPB8) in Motoneuron Diseases

Abstract

Amyotrophic lateral sclerosis (ALS) and spinal and bulbar muscular atrophy (SBMA) are two motoneuron diseases (MNDs) characterized by aberrant protein behavior in affected cells. In familial ALS (fALS) and in SBMA specific gene mutations lead to the production of neurotoxic proteins or peptides prone to misfold, which then accumulate in form of aggregates. Notably, some of these proteins accumulate into aggregates also in sporadic ALS (sALS) even if not mutated. To prevent proteotoxic stresses detrimental to cells, misfolded and/or aggregated proteins must be rapidly removed by the protein quality control (PQC) system. The small heat shock protein B8 (HSPB8) is a chaperone induced by harmful events, like proteasome inhibition. HSPB8 is expressed both in motoneuron and muscle cells, which are both targets of misfolded protein toxicity in MNDs. In ALS mice models, in presence of the mutant proteins, HSPB8 is upregulated both in spinal cord and muscle. HSPB8 interacts with the HSP70 co-chaperone BAG3 and enhances the degradation of misfolded proteins linked to sALS, or causative of fALS and of SBMA. HSPB8 acts by facilitating autophagy, thereby preventing misfolded protein accumulation in affected cells. BAG3 and BAG1 compete for HSP70-bound clients and target them for disposal to the autophagy or proteasome, respectively. Enhancing the selective targeting of misfolded proteins by HSPB8-BAG3-HSP70 to autophagy may also decrease their delivery to the proteasome by the BAG1-HSP70 complex, thereby limiting possible proteasome overwhelming. Thus, approaches aimed at potentiating HSPB8-BAG3 may contribute to the maintenance of proteostasis and may delay MNDs progression.

Quantitative assessment of the degradation of aggregated TDP‐43 mediated by the ubiquitin proteasome system and macroautophagy

“…Bag3 also interacts with HspB8 and competes for binding to Hsp70 and Stub1, which increases ALP degradation. The ratio between Bag1 and Bag3 expression levels indicated the preferential degradative pathway that was activated in the cells (43)(44)(45)(46)(47). These data demonstrate that neither HspB8 and Bag3, nor Bag1 mRNA expression were modified after transfection with control IBs and FL TDP-43 IBs compared with vehicle ( Fig.…”

Tdp-25 Routing to Autophagy and Proteasome Ameliorates its Aggregation in Amyotrophic Lateral Sclerosis Target Cells

“…In mammalian cells, the clearance of aberrantly folded or misfolded proteins is mediated by the intracellular protein quality control (PQC) system 11 . The PQC system is composed of chaperone/co-chaperone proteins, which recognize, bind to and target aberrant proteins to degradation, and the degradative systems, like the ubiquitin proteasome system and the autophagy 12 – 14 . Chaperones and co-chaperones work in complex; one example is represented by BAG3, a co-chaperone of HSP70 that also binds to the chaperone HSPB8, and the E3 ligase CHIP.…”

Silencing of BAG3 inhibits the epithelial-mesenchymal transition in human cervical cancer

“…BAG3, a member of six BAG families, contains a conserved domain, and interacts with Hsp-70 [ 6 – 9 ]. It has been reported that BAG3 is highly expressed in many kinds of primary tumors, including ovarian cancer, and glioblastoma [ 10 – 13 ].…”