Abstract
Skeletal muscle and the nervous system depend on efficient protein quality control, and they express chaperones and cochaperones at high levels to maintain protein homeostasis. Mutations in many of these proteins cause neuromuscular diseases, myopathies, and hereditary motor and sensorimotor neuropathies. In this review, we cover mutations in DNAJB6, DNAJB2, αB-crystallin (CRYAB, HSPB5), HSPB1, HSPB3, HSPB8, and BAG3, and discuss the molecular mechanisms by which they cause neuromuscular disease. In addition, previously unpublished results are presented, showing downstream effects of BAG3 p.P209L on DNAJB6 turnover and localization.
Highlights
Maintaining protein homeostasis is essential for cellular functioning
The results presented by Guilbert et al showed that BAG3 interacts with SQSTM1 independently of HSPB8 SQSTM1 [408], but the interaction between HSPB8 and BAG3 is required for the efficient coupling of SQSTM1 bodies (p62 bodies) for transport to aggresomes under proteasomal stress [408]
Wild-type but not p.P209L mutant BAG3 was suggested by zebrafish studies to augment the toxicity of mutant DNAJB6 [14]
Summary
This is demonstrated by the diversity of the molecular machinery evolved to maintain the protein homeostasis and by the pathologies associated with dysfunctional protein quality control (PQC) Chaperones, together with their essential cofactors known as cochaperones, assist their client proteins in attaining their native conformation, prevent unfolded or misfolded proteins from aggregation, and target damaged or superfluous proteins to degradative pathways [1]. E.g., the HSPA (Hsp70) family, consume ATP for client-binding cycles, whereas others, such as the small heat shock proteins (HSPB), are energy-independent [1,4] Cochaperones such as J-domain proteins (JDP, Hsp40) and BAG proteins assist chaperones in their functions, mediate interactions of the different chaperone families, and affect the fate of the client proteins [1,2]
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