Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2020 Feb 19;21(4):1409.
doi: 10.3390/ijms21041409.

Neuromuscular Diseases Due to Chaperone Mutations: A Review and Some New Results

Jaakko Sarparanta  1 , Per Harald Jonson  1 , Sabita Kawan  1 , Bjarne Udd  1   2   3
Affiliations
Review

Neuromuscular Diseases Due to Chaperone Mutations: A Review and Some New Results

Jaakko Sarparanta et al. Int J Mol Sci. .

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 In addition, previously unpublished results are presented, showing downstream effects of BAG3 p.P209L on DNAJB6 turnover and localization.

Keywords: J-domain protein; heat shock protein; myopathy; neuropathy; pathomechanism.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Figures

Figure 1
Figure 1
Interaction network of the discussed chaperones and cochaperones. Thick solid lines indicate interactions with established functional relevance. Dashed lines show detected interactions of unknown significance. The numbers indicate references [10,11,12,13,14,15,16,17,18,19,20].
Figure 2
Figure 2
Structure of DNAJB6 and mutations. (A) A schematic view of the DNAJB6 protein, with the various domains, and the alternatively spliced C-terminal parts of the “a” and “b” isoforms indicated. The inset shows the sequence of the glycine/phenylalanine-rich (G/F) domain, with the α5 helix and myopathy-causing mutations (pink arrows). (B) Protein structure of the J (orange) and G/F (green) domains, with residues harboring disease mutations shown. Structure from Protein Data Bank ID 6U3R [28].
Figure 3
Figure 3
Loss of antiaggregation effect due to DNAJB6 mutations. Various DNAJB6b constructs were tested in a filter trap assay for their ability to prevent the aggregation of polyQ huntingtin. Similarly to the previously tested p.F89I and p.F93L, both p.P96R and p.F100I mutations showed impaired antiaggregation activity. Wild-type DNAJB6a (a wt) and DNAJB6b (b wt) serve as negative and positive controls, respectively. The graph shows mean ± S.D. of eight to nine replicate transfections from three separate experiments. Asterisks indicate statistically significant differences to b wt according to the Mann–Whitney U test (** p < 0.01, *** p < 0.001).
Figure 4
Figure 4
The pathomechanism of DNAJB6 mutations. (A) Top: The suggested function of DNAJB6 in the HSPA cycle: (1) Client binding by DNAJB6. (2) HSPA binding to JD. (3) ATP hydrolysis and client transfer to HSPA. (4) Displacement of HSPA by the G/F domain. Adapted from [28]. Bottom: A model for the effect of myopathy mutations. The mutations interfere with the interaction between the J and G/F domains, leading to uncontrolled interaction with HSPA. (B) Possible parallel downstream pathways leading from DNAJB6 mutations to muscle disease.
Figure 5
Figure 5
Schematic structure of the DNAJB2 protein and the alternatively spliced C-terminal parts of the two isoforms. The J, G/F, and C-terminal (CTD) domains, the Ser/Thr-rich region, two ubiquitin-interacting motifs (UIM) and the C-terminal geranylgeranyl (GG) anchor of DNAJB2b are indicated.
Figure 6
Figure 6
Schematic structure of BAG3 with domains and motifs, and myopathy-causing mutations indicated. BAG3: Bcl-2-associated athanogene 3, or BAG family molecular chaperone regulator 3.
Figure 7
Figure 7
Effect of BAG3 p.P209L on DNAJB6. (A) Coexpression with BAG3 p.P209L similarly blocks the turnover of wild-type and p.F89I mutant DNAJB6b. Graph shows mean ± S.D. from 4–5 experiments performed in triplicate, with exponential trendlines fitted to the data points. (B) Representative Western blots showing DNAJB6b-V5 wt and p.F89I (V5) and tubulin (tub) levels at different time points. (C) Both DNAJB6a and DNAJB6b are recruited to cytoplasmic aggregates formed by BAG3 p.P209L in HeLa cells. (D) BAG3 p.P209L causes increased cytoplasmic localization of DNAJB6a in HeLa cells. Box plots show the cytoplasmic/nuclear V5 mean intensity ratio in n = 552–2291 cells per group.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Dekker S.L., Kampinga H.H., Bergink S. DNAJs: More than Substrate Delivery to HSPA. Front. Mol. Biosci. 2015;2:35. doi: 10.3389/fmolb.2015.00035. - DOI - PMC - PubMed
    1. Taipale M., Tucker G., Peng J., Krykbaeva I., Lin Z.Y., Larsen B., Choi H., Berger B., Gingras A.C., Lindquist S. A Quantitative Chaperone Interaction Network Reveals the Architecture of Cellular Protein Homeostasis Pathways. Cell. 2014;158:434–448. doi: 10.1016/j.cell.2014.05.039. - DOI - PMC - PubMed
    1. Freilich R., Arhar T., Abrams J.L., Gestwicki J.E. Protein-Protein Interactions in the Molecular Chaperone Network. Acc. Chem. Res. 2018;51:940–949. doi: 10.1021/acs.accounts.8b00036. - DOI - PMC - PubMed
    1. Carra S., Alberti S., Benesch J.L.P., Boelens W., Buchner J., Carver J.A., Cecconi C., Ecroyd H., Gusev N., Hightower L.E., et al. Small Heat Shock Proteins: Multifaceted Proteins with Important Implications for Life. Cell Stress Chaperones. 2019;24:295–308. doi: 10.1007/s12192-019-00979-z. - DOI - PMC - PubMed
    1. Shiber A., Ravid T. Chaperoning Proteins for Destruction: Diverse Roles of Hsp70 Chaperones and their Co-Chaperones in Targeting Misfolded Proteins to the Proteasome. Biomolecules. 2014;4:704–724. doi: 10.3390/biom4030704. - DOI - PMC - PubMed

MeSH terms