DNAJB6 is expressed in neurons and oligodendrocytes of the human brain.

Publisher: Wiley-Liss Country of Publication: United States NLM ID: 8806785 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1098-1136 (Electronic) Linking ISSN: 08941491 NLM ISO Abbreviation: Glia Subsets: MEDLINE

Publication: New York, NY : Wiley-Liss
Original Publication: New York : Alan R. Liss, Inc., c1988-

Oligodendroglia*/metabolism ; HSP40 Heat-Shock Proteins*/metabolism ; HSP40 Heat-Shock Proteins*/genetics ; Neurons*/metabolism ; Brain*/metabolism ; Nerve Tissue Proteins*/metabolism ; Molecular Chaperones*/metabolism; Humans ; Male ; Female ; Aged ; Middle Aged ; Aged, 80 and over ; Multiple System Atrophy/metabolism ; Multiple System Atrophy/pathology ; alpha-Synuclein/metabolism ; Parkinson Disease/metabolism ; Parkinson Disease/pathology ; Adult

DNAJB6 is a suppressor of α-synuclein aggregation in vivo and in vitro. DNAJB6 is strongly expressed in the brain, and its overall protein expression is altered in neurodegenerative conditions such as Parkinson's Disease (PD) and Multiple System Atrophy (MSA). These two diseases are characterized by accumulation of aggregated α-synuclein in neurons and oligodendrocytes, respectively. To further explore this, we employed post-mortem normal human brain material to investigate the regional and cell type specific protein expression of DNAJB6. We found that the DNAJB6 protein is ubiquitously expressed across various regions of the brain. Notably, we demonstrate for the first time that DNAJB6 is present in nearly half (41%-53%) of the oligodendrocyte population and in the majority (68%-80%) of neurons. However, DNAJB6 was only sparsely present in other cell types such as astrocytes and microglia. Given that α-synuclein aggregation in oligodendrocytes is a hallmark of MSA, we investigated DNAJB6 presence in MSA brains compared to control brains. We found no significant difference in the percentage of oligodendrocytes where DNAJB6 was present in MSA brains relative to control brains. In conclusion, our results reveal an expression of the DNAJB6 protein across various regions of the human brain, and that DNAJB6 is almost exclusively present in neurons and oligodendrocytes. Since prior studies have shown that PD and MSA brains have altered levels of DNAJB6 relative to control brains, DNAJB6 may be an interesting target for drug development.
(© 2024 Wiley Periodicals LLC.)

Ahmed, Z., Asi, Y. T., Lees, A. J., Revesz, T., & Holton, J. L. (2013). Identification and quantification of oligodendrocyte precursor cells in multiple system atrophy, progressive supranuclear palsy and Parkinson's disease. Brain Pathology, 23, 263–273. https://doi.org/10.1111/j.1750-3639.2012.00637.x.
Aprile, F. A., Källstig, E., Limorenko, G., Vendruscolo, M., Ron, D., & Hansen, C. (2017). The molecular chaperones DNAJB6 and Hsp70 cooperate to suppress α‐synuclein aggregation. Scientific Reports, 7, 9039. https://doi.org/10.1038/s41598-017-08324-z.
Arkan, S., Ljungberg, M., Kirik, D., & Hansen, C. (2021). DNAJB6 suppresses alpha‐synuclein induced pathology in an animal model of Parkinson's disease. Neurobiology of Disease, 158, 105477. https://doi.org/10.1016/j.nbd.2021.105477.
Braak, H., Sastre, M., & Del Tredici, K. (2007). Development of α‐synuclein immunoreactive astrocytes in the forebrain parallels stages of intraneuronal pathology in sporadic Parkinson's disease. Acta Neuropathologica, 114, 231–241. https://doi.org/10.1007/s00401-007-0244-3.
Brettschneider, J., Suh, E. R., Robinson, J. L., Fang, L., Lee, E. B., Irwin, D. J., Grossman, M., Van Deerlin, V. M., Lee, V. M. Y., & Trojanowski, J. Q. (2018). Converging patterns of α‐synuclein pathology in multiple system atrophy. Journal of Neuropathology and Experimental Neurology, 77, 1005–1016. https://doi.org/10.1093/jnen/nly080.
Chi, H., Chang, H. Y., & Sang, T. K. (2018). Neuronal cell death mechanisms in major neurodegenerative diseases. International Journal of Molecular Sciences. 19(10), 3082. https://doi.org/10.3390/ijms19103082.
Chuang, J. Z., Zhou, H., Zhu, M., Li, S. H., Li, X. J., & Sung, C. H. (2002). Characterization of a brain‐enriched chaperone, MRJ, that inhibits huntingtin aggregation and toxicity independently. Journal of Biological Chemistry, 277, 19831–19838. https://doi.org/10.1074/jbc.M109613200.
Deshayes, N., Arkan, S., & Hansen, C. (2019). The molecular chaperone DNAJB6, but not DNAJB1, suppresses the seeded aggregation of alpha‐synuclein in cells. International Journal of Molecular Sciences, 20(18), 4495. https://doi.org/10.3390/ijms20184495.
Durrenberger, P. F., Filiou, M. D., Moran, L. B., Michael, G. J., Novoselov, S., Cheetham, M. E., Clark, P., Pearce, R. K. B., & Graeber, M. B. (2009). DnaJB6 is present in the core of Lewy Bodies and is highly up‐regulated in Parkinsonian astrocytes. Journal of Neuroscience Research, 87, 238–245. https://doi.org/10.1002/jnr.21819.
Folke, J., Arkan, S., Martinsson, I., Aznar, S., Gouras, G., Brudek, T., & Hansen, C. (2021). DNAJB6b is downregulated in synucleinopathies. Journal of Parkinson's Disease, 11(4), 1791–1803. https://doi.org/10.3233/jpd-202512.
Gillis, J., Schipper‐Krom, S., Juenemann, K., Gruber, A., Coolen, S., Van Den Nieuwendijk, R., Van Veen, H., Overkleeft, H., Goedhart, J., Kampinga, H. H., & Reits, E. A. (2013). The DNAJB6 and DNAJB8 protein chaperones prevent intracellular aggregation of polyglutamine peptides. Journal of Biological Chemistry, 288(24), 17225–17237. https://doi.org/10.1074/jbc.M112.421685.
Goedert, M., Jakes, R., & Spillantini, M. G. (2017). The synucleinopathies: Twenty years on. Journal of Parkinson's Disease, 7(s1), S51–S69. https://doi.org/10.3233/JPD-179005.
Hageman, J., Rujano, M. A., van Waarde, M. A. W. H., Kakkar, V., Dirks, R. P., Govorukhina, N., Oosterveld‐Hut, H. M. J., Lubsen, N. H., & Kampinga, H. H. (2010). A DNAJB chaperone subfamily with HDAC‐dependent activities suppresses toxic protein aggregation. Molecular Cell, 37(3), 355–369. https://doi.org/10.1016/j.molcel.2010.01.001.
Hanai, R., & Mashima, K. (2003). Characterization of two isoforms of a human DnaJ homologue, HSJ2. Molecular Biology Reports, 30, 149–153. https://doi.org/10.1023/A:1024916223616.
Hsiao, J. H. T., Tanglay, O., Li, A. A., Strobbe, A. Y. G., Kim, W. S., Halliday, G. M., & Fu, Y. H. (2023). Role of oligodendrocyte lineage cells in multiple system atrophy. Cells, 12(5), 739. https://doi.org/10.3390/cells12050739.
Hunter, P. J., Swanson, B. J., Haendel, M. A., Lyons, G. E., & Cross, J. C. (1999). Mrj encodes a DnaJ‐related Co‐chaperone that is essential for murine placental development. Development, 126(6), 1247–1258. https://doi.org/10.1242/dev.126.6.1247.
Jellinger, K. A. (2018). Multiple system atrophy: An oligodendroglioneural synucleinopathy. Journal of Alzheimer's Disease, 62(3), 1141–1179. https://doi.org/10.3233/JAD-170397.
Kaji, S., Maki, T., Ueda, J., Ishimoto, T., Inoue, Y., Yasuda, K., Sawamura, M., Hikawa, R., Ayaki, T., Yamakado, H., & Takahashi, R. (2020). BCAS1‐positive immature oligodendrocytes are affected by the α‐synuclein‐induced pathology of multiple system atrophy. Acta Neuropathologica Communications, 8, 1–13. https://doi.org/10.1186/s40478-020-00997-4.
Kakkar, V., Månsson, C., de Mattos, E. P., Bergink, S., van der Zwaag, M., van Waarde, M. A. W. H., Kloosterhuis, N. J., Melki, R., van Cruchten, R. T. P., Al‐Karadaghi, S., Arosio, P., Dobson, C. M., Knowles, T. P. J., Bates, G. P., van Deursen, J. M., Linse, S., van de Sluis, B., Emanuelsson, C., & Kampinga, H. H. (2016). The S/T‐rich motif in the DNAJB6 chaperone delays polyglutamine aggregation and the onset of disease in a mouse model. Molecular Cell, 62(2), 272–283. https://doi.org/10.1016/j.molcel.2016.03.017.
Kampinga, H. H., Hageman, J., Vos, M. J., Kubota, H., Tanguay, R. M., Bruford, E. A., Cheetham, M. E., Chen, B., & Hightower, L. E. (2009). Guidelines for the nomenclature of the human heat shock proteins. Cell Stress and Chaperones, 14(1), 105–111. https://doi.org/10.1007/s12192-008-0068-7.
Koga, S., Sekiya, H., Kondru, N., Ross, O. A., & Dickson, D. W. (2021). Neuropathology and molecular diagnosis of synucleinopathies. Molecular Neurodegeneration, 16, 83. https://doi.org/10.1186/s13024-021-00501-z.
Månsson, C., Kakkar, V., Monsellier, E., Sourigues, Y., Härmark, J., Kampinga, H. H., Melki, R., & Emanuelsson, C. (2014). DNAJB6 is a peptide‐binding chaperone which can suppress amyloid fibrillation of Polyglutamine peptides at substoichiometric molar ratios. Cell Stress and Chaperones, 19(2), 227–239. https://doi.org/10.1007/s12192-013-0448-5.
May, V. E. L., Ettle, B., Poehler, A. M., Nuber, S., Ubhi, K., Rockenstein, E., Winner, B., Wegner, M., Masliah, E., & Winkler, J. (2014). α‐synuclein impairs oligodendrocyte progenitor maturation in multiple system atrophy. Neurobiology of Aging, 35, 2357–2368. https://doi.org/10.1016/j.neurobiolaging.2014.02.028.
Qiu, X. B., Shao, Y. M., Miao, S., & Wang, L. (2006). The diversity of the DnaJ/Hsp40 family, the crucial partners for Hsp70 chaperones. Cellular and Molecular Life Sciences, 63, 2560–2570. https://doi.org/10.1007/s00018-006-6192-6.
Richardson, W. D., Young, K. M., Tripathi, R. B., & McKenzie, I. (2011). NG2‐glia as multipotent neural stem cells: Fact or fantasy? Neuron, 70, 661–673. https://doi.org/10.1016/j.neuron.2011.05.013.
Rodríguez‐González, C., Lin, S., Arkan, S., & Hansen, C. (2020). Co‐chaperones DNAJA1 and DNAJB6 are critical for regulation of Polyglutamine aggregation. Scientific Reports, 10, 8130. https://doi.org/10.1038/s41598-020-65046-5.
Schindelin, J., Arganda‐Carreras, I., Frise, E., Kaynig, V., Longair, M., Pietzsch, T., Preibisch, S., Rueden, C., Saalfeld, S., Schmid, B., Tinevez, J. Y., White, D. J., Hartenstein, V., Eliceiri, K., Tomancak, P., & Cardona, A. (2012). Fiji: An open‐source platform for biological‐image analysis. Nature Methods, 9, 676–682. https://doi.org/10.1038/nmeth.2019.
Seki, N., Hattori, A., Hayashi, A., Kozuma, S., Miyajima, N., & Saito, T. (1999). Cloning, tissue expression, and chromosomal assignment of human MRJ gene for a member of the DNAJ protein family. Journal of Human Genetics, 44, 185–189. https://doi.org/10.1007/s100380050139.
Spillantini, M. G., Schmidt, M. L., Lee, V. M. Y., Trojanowski, J. Q., Jakes, R., & Goedert, M. (1997). α‐synuclein in Lewy Bodies. Nature, 388, 839–840. https://doi.org/10.1038/42166.
Summers, D. W., Douglas, P. M., Ramos, C. H. I., & Cyr, D. M. (2009). Polypeptide transfer from Hsp40 to Hsp70 molecular chaperones. Trends in Biochemical Sciences, 34(5), 230–233. https://doi.org/10.1016/j.tibs.2008.12.009.

R53-A1356-B545 Parkinsonforeningen

Keywords: DNAJB6; chaperones; clinical samples; human brain; oligodendrocytes; α‐synuclein

0 (HSP40 Heat-Shock Proteins)
0 (DNAJB6 protein, human)
0 (Nerve Tissue Proteins)
0 (Molecular Chaperones)
0 (alpha-Synuclein)

Date Created: 20240904 Date Completed: 20241030 Latest Revision: 20241105

20241106

10.1002/glia.24615

39228066