Chaperone Assisted Selective Autophagy (CASA) a potential target for therapeutics in motoneuron diseases

Misfolded proteins are a common hallmark of motoneuron diseases (MNDs) including amyotrophic lateral sclerosis (ALS) and spinal and bulbar muscular atrophy (SBMA). Misfolded proteins may form aggregate and cause motoneuron death and muscle atrophy. Dysfunctions of the protein quality control (PQC) system have been suggested to contribute to protein aggregation. Indeed, the PQC system assists protein folding by chaperones and if this fails the PQC promotes protein degradation via proteasome and/or autophagy to maintain normal protein homeostasis. A peculiar form of autophagy, initially identified in the muscle is the chaperone-assisted selective autophagy (CASA). CASA is one of the two arms of the routing system controlling the delivery of misfolded proteins to proteasome and autophagy. CASA differs from chaperone mediated autophagy (CMA) because it delivers misfolded proteins directly to autophagosomes, instead of to lysosomes as in CMA. CASA is mediated by the CASA complex, which comprises molecular chaperones (HSPB8 and HSPA8), a co-chaperones (BAG3) and an E3-uniquitin ligase (STUB1). HSPB8 and BAG3 are boud togetehr and interact with misfolded proteins recognized by HSPA8 allowing the STUB1 mediated ubiquitination of misfolded proteins. This allows the insertion of p62 tagged and ubiquitinated misfolded proteins into autophagosomes. In our lab we found that the CASA complex has an important role in motoneuron protection against misfolded proteins toxicity. We demonstrated that HSPB8 overexpression is sufficient to increase the degradation of misfolded proteins responsible for ALS (G93A SOD1; mutTDP-43; C9ORF72 DPRs) and SBMA (ARpolyQ). Since that, we have developed different research line aimed to identify molecular mechanisms that alter proteins homeostasis in motoneurons and muscle cells to: a. study the HSPB8 single point mutations identified in ALS and other neuromuscular diseases. b. develop models useful to study HSPB8 transcriptional regulation and HSPB8 stability. c. study trehalose activity as possible compound to treat SBMA by its capability to activate CASA. d. study the role of dynein mediated transport of CASA complex in the routing system. e. the role of CASA in muscle tissues in ALS and SBMA. All data collected show that HSPB8 plays a central role in the CASA misfolded protein degradation. Indeed, we showed that in all models studied, HspB8 was able to reduce the aggregation of the misfolded proteins analyzed. Moreover, the pharmacological induction of HSPB8 (by mean of trehalose and colchicine) plays a beneficial role against misfolded protein aggregation.