HSPB8-related neuromuscular diseases

Ondertitel:from mechanisms to treatment strategies

Small heat shock proteins are molecular chaperones that aid in preventing protein aggregation. They can rapidly recognize and bind unfolded or misfolded proteins, and keep them in a folding-competent state until large heat shock proteins like HSP70 complete the refolding process. When proper folding fails, small heat shock proteins aid in the clearance of these aberrant protein products by routing them to one of the degradation systems. Mutations in the small heat shock proteins B1 (HSPB1/Hsp27) and B8 (HSPB8/Hsp22) mainly cause Charcot-Marie-Tooth (CMT) disease or distal hereditary motor neuropathy (dHMN), disorders characterized by degeneration of the peripheral nerves. With no cure available, developing new therapeutic strategies as well as improving our understanding of the (patho)mechanisms of small heat shock proteins is of utmost importance. In this thesis, we took advantage of our in-house Hspb8 mouse models to test if suppression of Hspb8 mRNA can alleviate disease symptoms, as the lack of Hspb8 seems to be well tolerated in mice. Although preliminary in vivo results hint towards functional improvement, additional experiments are required to elucidate the full potential of Hspb8 silencing. In neuronal cultures derived from induced pluripotent stem cells from patients, mitochondrial morphology was rescued by reducing HSPB8 expression. Together with the co-chaperone BAG3, HSP70, and the E3 ubiquitin ligase CHIP, HSPB8 functions in chaperone-assisted selective autophagy (CASA), a selective degradation pathway for ubiquitinated substrates. Although most point mutations in HSPB8 target the conserved lysine 141 residue, a set of frameshift mutations linked with myopathies preferentially reside in its C-terminus. These mutations result in an elongated, aggregation-prone protein product, suggested to impair the CASA pathway thereby triggering insufficient clearance of misfolded substrates. In this thesis we studied the functional consequences of these frameshift mutations and found that they drastically reduce the solubility of HSPB8, leading to cytosolic aggregate formation. In addition, mutant HSPB8 trapped the other CASA complex members, along with autophagic receptors, resulting in a general collapse of the chaperone network. In summary, this thesis contributed to the first step toward the development of a treatment for HSPB8-related diseases. In addition, we broadened the current understanding of the pathomechanism of a group of frameshift mutations in the C-terminus of HSPB8. Further studies will be required to address the remaining open questions regarding their pathomechanism and muscle-specific vulnerability.

Jaar van publicatie:2022

Trefwoorden:Doctoral thesis

Toegankelijkheid:Closed