The Role of Small Heat Shock Proteins in Protein Misfolding Associated Motoneuron Diseases

Abstract

Motoneuron diseases (MNDs) are neurodegenerative conditions associated with death of upper and/or lower motoneurons (MNs). Proteostasis alteration is a pathogenic mechanism involved in many MNDs and is due to the excessive presence of misfolded and aggregated proteins. Protein misfolding may be the product of gene mutations, or due to defects in the translation process, or to stress agents; all these conditions may alter the native conformation of proteins making them prone to aggregate. Alternatively, mutations in members of the protein quality control (PQC) system may determine a loss of function of the proteostasis network. This causes an impairment in the capability to handle and remove aberrant or damaged proteins. The PQC system consists of the degradative pathways, which are the autophagy and the proteasome, and a network of chaperones and co-chaperones. Among these components, Heat Shock Protein 70 represents the main factor in substrate triage to folding, refolding, or degradation, and it is assisted in this task by a subclass of the chaperone network, the small heat shock protein (sHSPs/HSPBs) family. HSPBs take part in proteostasis by bridging misfolded and aggregated proteins to the HSP70 machinery and to the degradative pathways, facilitating refolding or clearance of the potentially toxic proteins. Because of its activity against proteostasis alteration, the chaperone system plays a relevant role in the protection against proteotoxicity in MNDs. Here, we discuss the role of HSPBs in MNDs and which HSPBs may represent a valid target for therapeutic purposes.

Secreted Metabolome of ALS-Related hSOD1(G93A) Primary Cultures of Myocytes and Implications for Myogenesis

“…Skeletal muscle represents the main tissue for glutamine synthesis, storage, and release [74]. Glutamine has antioxidant (as a precursor of glutathione) and anti-inflammatory properties, modulates the synthesis of shock proteins [74], which are implicated in the response to the proteostatic stress in ALS and other neurodegenerative disorders [75], and participates in skeletal muscle differentiation [76]. However, during catabolic situations, as might occur in the muscle of ALS patients [74,77], glutamine concentration in plasma and tissues (especially in skeletal muscle) is severely compromised [78].…”

Current insights in the molecular genetic pathogenesis of amyotrophic lateral sclerosis

“…The chaperon-assisted proteasome degradation is a system that facilitates the degradation of abnormal proteins by bridging misfolded and aggregated proteins to heat shock protein 70 (HSP70). This system participates in maintaining the protein homeostasis and promotes the refolding or removal of potentially toxic proteins ( Tedesco et al, 2022 ). It has been found that heat shock proteins are encapsulated in the SOD1-positive aggregates, which reduces their ability to process the misfolded proteins in ALS ( Farrawell and Yerbury, 2021 ).…”

Sequential expression of small heat shock proteins contributing to the cold response of Haemaphysalis longicornis (Acari: Ixodidae)

“…16 sHsps known as 'housekeeping' proteins represent a group of highly conserved molecular chaperones that bind to misfolded proteins during stress conditions to prevent irreversible protein unfolding or aggregation, thereby maintaining protein homeostasis. [17][18][19] sHsps perform their chaperone-like activity in an ATP-independent manner. 18 sHsps have been widely studied in ticks.…”

“…In addition, they are involved in protein folding, assembly, secretion, and degradation as well as the regulation of various cellular functions in organisms 16 . sHsps known as ‘housekeeping’ proteins represent a group of highly conserved molecular chaperones that bind to misfolded proteins during stress conditions to prevent irreversible protein unfolding or aggregation, thereby maintaining protein homeostasis 17–19 . sHsps perform their chaperone‐like activity in an ATP‐independent manner 18 .…”