Knockdown of Rab9 Recovers Defective Morphological Differentiation Induced by Chemical ER Stress Inducer or PMD-Associated PLP1 Mutant Protein in FBD-102b Cells

Overview

Journal Pathophysiology

Publisher MDPI

Specialty Pathology

Date 2024 Sep 23

PMID 39311306

Authors

Nana Fukushima

Yuki Miyamoto

Junji Yamauchi

Affiliations

Soon will be listed here.

Abstract

Small GTP-binding proteins of the Rab family regulate intracellular vesicle trafficking across many aspects of the transport system. Among these, Rab9 is recognized for its role in controlling the transport system not only around the trans-Golgi network but also around the late endosome. However, the specific functions across different cell types and tissues remain unclear. Here, for the first time, we report that Rab9 negatively regulates morphological changes in the FBD-102b cell line, an oligodendroglial precursor cell line undergoing morphological differentiation. The knockdown of Rab9 led to an increase in cell shape alterations characterized by widespread membrane extensions. These changes were accompanied by increased expression levels of oligodendroglial cell differentiation and myelination marker proteins. Notably, the knockdown of Rab9 was capable of recovering defective cell morphological changes induced by tunicamycin, an inducer of endoplasmic reticulum (ER) stress, which is one of the major causes of oligodendroglial cell diseases such as Pelizaeus-Merzbacher disease (PMD, currently known as hypomyelinating leukodystrophy type 1 [HLD1]). In addition, Rab9 knockdown recovered levels of ER stress marker proteins and differentiation markers. Similar results were obtained in the cases of dithiothreitol (DTT), another chemical ER stress inducer, as well as HLD1-associated proteolipid protein 1 (PLP1) mutant protein. These results indicate a unique role for Rab9 in oligodendroglial cell morphological changes, suggesting its potential as a therapeutic target for mitigating diseases such as HLD1 at the molecular and cellular levels.

References

Anitei M, Cowan A, Pfeiffer S, Bansal R . Role for Rab3a in oligodendrocyte morphological differentiation. J Neurosci Res. 2008; 87(2):342-52. DOI: 10.1002/jnr.21870. View

Kim S, Woo C . Laminar Flow Inhibits ER Stress-Induced Endothelial Apoptosis through PI3K/Akt-Dependent Signaling Pathway. Mol Cells. 2018; 41(11):964-970. PMC: 6277562. DOI: 10.14348/molcells.2018.0111. View

Baumann N, Pham-Dinh D . Biology of oligodendrocyte and myelin in the mammalian central nervous system. Physiol Rev. 2001; 81(2):871-927. DOI: 10.1152/physrev.2001.81.2.871. View

Simons M, Lyons D . Axonal selection and myelin sheath generation in the central nervous system. Curr Opin Cell Biol. 2013; 25(4):512-9. DOI: 10.1016/j.ceb.2013.04.007. View

Barbero P, Bittova L, Pfeffer S . Visualization of Rab9-mediated vesicle transport from endosomes to the trans-Golgi in living cells. J Cell Biol. 2002; 156(3):511-8. PMC: 2173336. DOI: 10.1083/jcb.200109030. View

Ao X, Zou L, Wu Y . Regulation of autophagy by the Rab GTPase network. Cell Death Differ. 2014; 21(3):348-58. PMC: 3921601. DOI: 10.1038/cdd.2013.187. View

Wilmes S, Kummel D . Insights into the role of the membranes in Rab GTPase regulation. Curr Opin Cell Biol. 2023; 83:102177. DOI: 10.1016/j.ceb.2023.102177. View

Healy S, McMahon J, Fitzgerald U . UPR Induction Prevents Iron Accumulation and Oligodendrocyte Loss in Cultured Hippocampal Slices. Front Neurosci. 2019; 12:969. PMC: 6305600. DOI: 10.3389/fnins.2018.00969. View

Dhaunchak A, Colman D, Nave K . Misalignment of PLP/DM20 transmembrane domains determines protein misfolding in Pelizaeus-Merzbacher disease. J Neurosci. 2011; 31(42):14961-71. PMC: 6623585. DOI: 10.1523/JNEUROSCI.2097-11.2011. View

10.

Paira S, Chakraborty A, Das B . The Sequential Recruitments of Rab-GTPase Ypt1p and the NNS Complex onto pre- mRNA Promote Its Nuclear Degradation in Baker's Yeast. Mol Cell Biol. 2023; 43(8):371-400. PMC: 10448977. DOI: 10.1080/10985549.2023.2227016. View

11.

Lombardi D, Soldati T, Riederer M, Goda Y, Zerial M, Pfeffer S . Rab9 functions in transport between late endosomes and the trans Golgi network. EMBO J. 1993; 12(2):677-82. PMC: 413253. DOI: 10.1002/j.1460-2075.1993.tb05701.x. View

12.

Barnes-Velez J, Aksoy Yasar F, Hu J . Myelin lipid metabolism and its role in myelination and myelin maintenance. Innovation (Camb). 2023; 4(1):100360. PMC: 9800635. DOI: 10.1016/j.xinn.2022.100360. View

13.

Oakes S, Papa F . The role of endoplasmic reticulum stress in human pathology. Annu Rev Pathol. 2014; 10:173-94. PMC: 5568783. DOI: 10.1146/annurev-pathol-012513-104649. View

14.

Morimura T, Numata Y, Nakamura S, Hirano E, Gotoh L, Goto Y . Attenuation of endoplasmic reticulum stress in Pelizaeus-Merzbacher disease by an anti-malaria drug, chloroquine. Exp Biol Med (Maywood). 2014; 239(4):489-501. DOI: 10.1177/1535370213520108. View

15.

Bouverat B, Krueger W, Coetzee T, Bansal R, Pfeiffer S . Expression of rab GTP-binding proteins during oligodendrocyte differentiation in culture. J Neurosci Res. 2000; 59(3):446-53. DOI: 10.1002/(SICI)1097-4547(20000201)59:3<446::AID-JNR20>3.0.CO;2-L. View

16.

Torisu H, Iwaki A, Takeshita K, Hiwatashi A, Sanefuji M, Fukumaki Y . Clinical and genetic characterization of a 2-year-old boy with complete PLP1 deletion. Brain Dev. 2012; 34(10):852-6. DOI: 10.1016/j.braindev.2012.02.006. View

17.

Schinzel R, Higuchi-Sanabria R, Shalem O, Moehle E, Webster B, Joe L . The Hyaluronidase, TMEM2, Promotes ER Homeostasis and Longevity Independent of the UPR. Cell. 2019; 179(6):1306-1318.e18. PMC: 6913896. DOI: 10.1016/j.cell.2019.10.018. View

18.

Dobson R, Giovannoni G . Multiple sclerosis - a review. Eur J Neurol. 2018; 26(1):27-40. DOI: 10.1111/ene.13819. View

19.

Hetz C, Saxena S . ER stress and the unfolded protein response in neurodegeneration. Nat Rev Neurol. 2017; 13(8):477-491. DOI: 10.1038/nrneurol.2017.99. View

20.

Garbern J, Cambi F, Shy M, Kamholz J . The molecular pathogenesis of Pelizaeus-Merzbacher disease. Arch Neurol. 1999; 56(10):1210-4. DOI: 10.1001/archneur.56.10.1210. View