Different Mutations of Gap Junction Connexin 47 Lead to Discrepant Activation of Unfolded Protein Response Pathway in Pelizaeus–Merzbacher-Like Disease
24 February 2017
23 May 2017
16 July 2017 (eFirst)
Background The unfolded protein response (UPR) includes three cascade pathways, which are responsible for the elimination of overload protein that is accumulated in the endoplasmic reticulum (ER). We hypothesize that mutations in connexin 47 (Cx47) lead to abnormal retain of the protein in the ER lumen, which causes Pelizaeus–Merzbacher-like disease (PMLD), a hypomyelinating leukodystrophic disorder.
Methods In this study, the influence of mutant Cx47 on the three UPR cascade pathways and discrepant UPR activation was analyzed in an oligodendrocyte cell line transfected with different mutations in the first extracellular loop of Cx47. As over activated UPR pathway would lead to cell apoptosis, cell viability and apoptosis were also compared between the different mutants.
Results The elevated UPR level accompanied with higher apoptotic rates were measured in the c.138C > G or c.217C > T-transduced oligodendrocytes, but not in the c.216delGinsAA group, compared with the wild-type and empty vector groups. Cell viability was lower in oligodendrocytes transfected with the mutation of c.138C > G or c.217C > T, but not in the c.216delGinsAA group.
Conclusion Different mutations in the Cx47 lead to discrepant activation of UPR pathway, which encouraged apoptotic cell death at different levels. Inappropriate activation of UPR may play important roles in the pathophysiology of PMLD.
The authors declare that they have no competing interests.
- 1 Nualart-Marti A, Solsona C, Fields RD. Gap junction communication in myelinating glia. Biochim Biophys Acta 2013; 1828 (01) 69-78
- 2 Uhlenberg B, Schuelke M, Rüschendorf F. , et al. Mutations in the gene encoding gap junction protein alpha 12 (connexin 46.6) cause Pelizaeus-Merzbacher-like disease. Am J Hum Genet 2004; 75 (02) 251-260
- 3 Inoue K. PLP1-related inherited dysmyelinating disorders: Pelizaeus-Merzbacher disease and spastic paraplegia type 2. Neurogenetics 2005; 6 (01) 1-16
- 4 Kim MS, Gloor GB, Bai D. The distribution and functional properties of Pelizaeus-Merzbacher-like disease-linked Cx47 mutations on Cx47/Cx47 homotypic and Cx47/Cx43 heterotypic gap junctions. Biochem J 2013; 452 (02) 249-258
- 5 Orthmann-Murphy JL, Enriquez AD, Abrams CK, Scherer SS. Loss-of-function GJA12/Connexin47 mutations cause Pelizaeus-Merzbacher-like disease. Mol Cell Neurosci 2007; 34 (04) 629-641
- 6 Diekmann S, Henneke M, Burckhardt BC, Gärtner J. Pelizaeus-Merzbacher-like disease is caused not only by a loss of connexin47 function but also by a hemichannel dysfunction. Eur J Hum Genet 2010; 18 (09) 985-992
- 7 Miyamoto Y, Torii T, Eguchi T, Nakamura K, Tanoue A, Yamauchi J. Hypomyelinating leukodystrophy-associated missense mutant of FAM126A/hyccin/DRCTNNB1A aggregates in the endoplasmic reticulum. J Clin Neurosci 2014; 21 (06) 1033-1039
- 8 Wiseman RL, Haynes CM, Ron D. SnapShot: The unfolded protein response. Cell 2010; 140 (04) 590-590.e2
- 9 Kondo S, Hino SI, Saito A. , et al. Activation of OASIS family, ER stress transducers, is dependent on its stabilization. Cell Death Differ 2012; 19 (12) 1939-1949
- 10 Ariyasu D, Yoshida H, Hasegawa Y. Endoplasmic Reticulum (ER) Stress and Endocrine Disorders. Int J Mol Sci 2017; 18 (02) E382
- 11 Osaka H, Hamanoue H, Yamamoto R. , et al. Disrupted SOX10 regulation of GJC2 transcription causes Pelizaeus-Merzbacher-like disease. Ann Neurol 2010; 68 (02) 250-254
- 12 Hobson GM, Garbern JY. Pelizaeus-Merzbacher disease, Pelizaeus-Merzbacher-like disease 1, and related hypomyelinating disorders. Semin Neurol 2012; 32 (01) 62-67
- 13 Schiffmann R, van der Knaap MS. Invited article: an MRI-based approach to the diagnosis of white matter disorders. Neurology 2009; 72 (08) 750-759
- 14 Southwood C, Gow A. Molecular pathways of oligodendrocyte apoptosis revealed by mutations in the proteolipid protein gene. Microsc Res Tech 2001; 52 (06) 700-708
- 15 Wang J, Wang H, Wang Y, Chen T, Wu X, Jiang Y. Two novel gap junction protein alpha 12 gene mutations in two Chinese patients with Pelizaeus-Merzbacher-like disease. Brain Dev 2010; 32 (03) 236-243
- 16 Harding HP, Zhang Y, Zeng H. , et al. An integrated stress response regulates amino acid metabolism and resistance to oxidative stress. Mol Cell 2003; 11 (03) 619-633
- 17 Benavides A, Pastor D, Santos P, Tranque P, Calvo S. CHOP plays a pivotal role in the astrocyte death induced by oxygen and glucose deprivation. Glia 2005; 52 (04) 261-275
- 18 Marciniak SJ, Yun CY, Oyadomari S. , et al. CHOP induces death by promoting protein synthesis and oxidation in the stressed endoplasmic reticulum. Genes Dev 2004; 18 (24) 3066-3077
- 19 Mori K, Ogawa N, Kawahara T, Yanagi H, Yura T. mRNA splicing-mediated C-terminal replacement of transcription factor Hac1p is required for efficient activation of the unfolded protein response. Proc Natl Acad Sci U S A 2000; 97 (09) 4660-4665
- 20 Adachi Y, Yamamoto K, Okada T, Yoshida H, Harada A, Mori K. ATF6 is a transcription factor specializing in the regulation of quality control proteins in the endoplasmic reticulum. Cell Struct Funct 2008; 33 (01) 75-89