234th ENMC International Workshop: Chaperone dysfunction in muscle disease Naarden, The Netherlands, 8–10 December 2017

Ben‐Zvi, Anat; Blaettler, Thomas; Bryson-Richardson, Robert; Carra, Serena; Dimachkie, Mazen M.; Findlay, Andrew; Greensmith, Linda; Greenspan, Stephen; Hanna, Michael G.; Höhfled, Jörg; Jonson, Per Harald; Kampinga, Harm H.; Larsson, Lars; Linke, Wolfgang A.; Lynch, Gonrdon; Machado, Pedro; Orlando, Lianna; Richard, Isabelle; Roos, Andreas; Sarparanta, J.; Timmerman, Vincent; Udd, Bjarne; Weihl, Conrad C.; Zah, Laura

doi:10.1016/j.nmd.2018.09.004

Cited by 9 publications

(8 citation statements)

References 31 publications

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“…This results in the accumulation of aggregated proteins that sequester important protein quality control (PQC) factors, including Hsp70. Importantly, accumulation of aggregated proteins has been documented in the biopsies of patients affected by myopathy and peripheral neuropathy 24,28 , further supporting the interpretation that these mutations may affect BAG3 PQC functions.…”

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confidence: 60%

BAG3 Pro209 mutants associated with myopathy and neuropathy relocate chaperones of the CASA-complex to aggresomes

Adriaenssens

Tedesco

Mediani

et al. 2020

Sci Rep

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Three missense mutations targeting the same proline 209 (Pro209) codon in the co-chaperone Bcl2associated athanogene 3 (BAG3) have been reported to cause distal myopathy, dilated cardiomyopathy or Charcot-Marie-Tooth type 2 neuropathy. Yet, it is unclear whether distinct molecular mechanisms underlie the variable clinical spectrum of the rare patients carrying these three heterozygous Pro209 mutations in BAG3. Here, we studied all three variants and compared them to the BAG3_Glu455Lys mutant, which causes dilated cardiomyopathy. We found that all BAG3_Pro209 mutants have acquired a toxic gain-of-function, which causes these variants to accumulate in the form of insoluble HDAC6-and vimentin-positive aggresomes. The aggresomes formed by mutant BAG3 led to a relocation of other chaperones such as HSPB8 and Hsp70, which, together with BAG3, promote the so-called chaperoneassisted selective autophagy (CASA). As a consequence of their increased aggregation-proneness, mutant BAG3 trapped ubiquitinylated client proteins at the aggresome, preventing their efficient clearance. Combined, these data show that all BAG3_Pro209 mutants, irrespective of their different clinical phenotypes, are characterized by a gain-of-function that contributes to the gradual loss of protein homeostasis. Protein homeostasis is maintained by a complex network of molecular chaperones and co-chaperones providing protection to client proteins at every stage of their lifetime 1. As soon as a nascent polypeptide leaves the ribosomal exit tunnel, chaperones interact with exposed domains to facilitate protein folding 2. In case of protein misfolding, chaperones will either try to refold or guide the polypeptide towards degradation by proteasomes or the autophagy-lysosomal pathway 1. The activity of many chaperones is critically dependent on co-chaperones. One family of co-chaperones is represented by the Bcl2-associated athanogene (BAG) family of proteins, which in humans includes six members, encoded by 6 different genes 3. All six family members share a conserved BAG-domain, which is essential for their binding to the Hsp70 chaperones 4. BAG3 is a well-characterized family member that contains a number of additional protein domains besides the conserved BAG-domain, including two Ile-Pro-Val (IPV)-motifs, a PxxP domain and a WW-domain (Fig. 1a). Each of these domains is known to have specific interacting partners. For instance, the BAG-domain is known to mediate the interaction with Hsp70/Hsc70 or Bcl2 5-7. The IPV-motifs have been shown to be indispensable for binding to small heat shock proteins (sHSPs) 8 , the WW-domain binds LATS1 9 , and the PxxP domain is necessary for the interaction with dynein and PLC-γ 10,11. The sHSP with the highest affinity for the IPV-motifs of BAG3 is HSPB8 (Hsp22) 12,13. In fact, the protein stability of HSPB8 is critically dependent on BAG3, as it is rapidly degraded in its absence 14. As also other members of the HSPB family are capable of binding to BAG3, it is thought that in case HSPB8 would be unable to fulfil its

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confidence: 60%

BAG3 Pro209 mutants associated with myopathy and neuropathy relocate chaperones of the CASA-complex to aggresomes

Adriaenssens

Tedesco

Mediani

et al. 2020

Sci Rep

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“…The continued dissolution of the myofibrillar structure, which clinically manifests as progressive muscle weakness, is characteristic of the chaperone dysfunction in forms of childhood-onset dystrophy. 8 Pathologically, this disorder could be considered a myofibrillar dystrophy because the excessive nuclear centralization seen on histology is a marker of an activated regenerative process. This is in contrast to a sarcolemmal dystrophic process, which typically leads to a more inflammatory and fibrotic picture, leading to an excessive matrix and fat proliferation.…”

Section: Discussionmentioning

confidence: 99%

“…7 These examples suggest that abnormal chaperone function is an important driver in neuromuscular disease, suggesting that its correction might be a valid therapeutic approach. 8 The abovementioned chaperones are involved in the proper folding and stability of aggregation-prone proteins in various cell types, including muscle. In contrast to the broad functional spectrum of many molecular chaperones, more specialized chaperone systems regulate muscle contraction by folding and assembling of conventional type II myosin.…”

Section: Introductionmentioning

confidence: 99%

Pathogenic Variants in the Myosin Chaperone UNC-45B Cause Progressive Myopathy with Eccentric Cores

Donkervoort

Kutzner

et al. 2020

The American Journal of Human Genetics

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The myosin-directed chaperone UNC-45B is essential for sarcomeric organization and muscle function from Caenorhabditis elegans to humans. The pathological impact of UNC-45B in muscle disease remained elusive. We report ten individuals with bi-allelic variants in UNC45B who exhibit childhood-onset progressive muscle weakness. We identified a common UNC45B variant that acts as a complex hypomorph splice variant. Purified UNC-45B mutants showed changes in folding and solubility. In situ localization studies further demonstrated reduced expression of mutant UNC-45B in muscle combined with abnormal localization away from the A-band towards the Z-disk of the sarcomere. The physiological relevance of these observations was investigated in C. elegans by transgenic expression of conserved UNC-45 missense variants, which showed impaired myosin binding for one and defective muscle function for three. Together, our results demonstrate that UNC-45B impairment manifests as a chaperonopathy with progressive muscle pathology, which discovers the previously unknown conserved role of UNC-45B in myofibrillar organization.

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“…Mutations in chaperone or co-chaperone genes cause neuromuscular diseases, termed chaperonopathies 1, 6 . Previous studies found that mutations in CRYAB 7 , HSPB8 8 , BAG3 9 , DNAJB6 10 , or SIL1 11, 12 cause protein aggregate myopathies including myofibrillar myopathy, rimmed vacuolar myopathy, limb girdle muscular dystrophy (LGMD) D1 or Marinesco-Sjögren syndrome, respectively.…”

Section: Introductionmentioning

confidence: 99%

“…Previous studies found that mutations in CRYAB 7 , HSPB8 8 , BAG3 9 , DNAJB6 10 , or SIL1 11, 12 cause protein aggregate myopathies including myofibrillar myopathy, rimmed vacuolar myopathy, limb girdle muscular dystrophy (LGMD) D1 or Marinesco-Sjögren syndrome, respectively. A common pathogenic process is the functional disturbance of the molecular chaperone systems by the genetic variants leading to aggregation of misfolded proteins in myofibers and subsequent muscle degeneration 6, 13 . However, the precise pathomechanism, including the identity of client proteins, the contents and properties of the cytoplasmic aggregates, their toxicities and consequent effects, and the response of myofibers, has not been completely clarified in these myopathies.…”

Section: Introductionmentioning

confidence: 99%

Distinctive chaperonopathy in skeletal muscle associated with the dominant variant inDNAJB4

Inoue

Noguchi

Inoue

et al. 2022

Preprint

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DnaJ homolog, subfamily B, member 4, a member of the heat shock protein 40 chaperones encoded by DNAJB4, is highly expressed in myofibers. We identified a heterozygous c.270 T>A (p.F90L) variant in DNAJB4 in a family with a dominantly inherited distal myopathy, in which affected members have specific features on muscle pathology represented by the presence of cytoplasmic inclusions and the accumulation of desmin, p62, HSP70 and DNAJB4 predominantly in type 1 fibers. Both Dnajb4-F90L knock-in and knockout mice developed muscle weakness and recapitulated the patient muscle pathology in the soleus muscle, where DNAJB4 has the highest expression. These data indicate that the identified variant is causative resulting in defective chaperone function and selective muscle degeneration in specific muscle fibers. This study demonstrates the importance of DNAJB4 in skeletal muscle proteostasis by identifying the associated chaperonopathy.

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234th ENMC International Workshop: Chaperone dysfunction in muscle disease Naarden, The Netherlands, 8–10 December 2017

Cited by 9 publications

References 31 publications

BAG3 Pro209 mutants associated with myopathy and neuropathy relocate chaperones of the CASA-complex to aggresomes

BAG3 Pro209 mutants associated with myopathy and neuropathy relocate chaperones of the CASA-complex to aggresomes

Pathogenic Variants in the Myosin Chaperone UNC-45B Cause Progressive Myopathy with Eccentric Cores

Distinctive chaperonopathy in skeletal muscle associated with the dominant variant inDNAJB4

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