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Rab18 Collaborates with Rab7 to Modulate Lysosomal and Autophagy Activities in the Nervous System: an Overlapping Mechanism for Warburg Micro Syndrome and Charcot-Marie-Tooth Neuropathy Type 2B

  • Fang-Shin Nian
  • Lei-Li Li
  • Chih-Ya Cheng
  • Pei-Chun Wu
  • You-Tai Lin
  • Cheng-Yung Tang
  • Bo-Shiun Ren
  • Chin-Yin Tai
  • Ming-Ji Fann
  • Lung-Sen Kao
  • Chen-Jee Hong
  • Jin-Wu TsaiEmail author
Article

Abstract

Mutations in RAB18, a member of small G protein, cause Warburg micro syndrome (WARBM), whose clinical features include vision impairment, postnatal microcephaly, and lower limb spasticity. Previously, our Rab18−/− mice exhibited hind limb weakness and spasticity as well as signs of axonal degeneration in the spinal cord and lumbar spinal nerves. However, the cellular and molecular function of RAB18 and its roles in the pathogenesis of WARBM are still not fully understood. Using immunofluorescence staining and expression of Rab18 and organelle markers, we find that Rab18 associates with lysosomes and actively traffics along neurites in cultured neurons. Interestingly, Rab18−/− neurons exhibit impaired lysosomal transport. Using autophagosome marker LC3-II, we show that Rab18 dysfunction leads to aberrant autophagy activities in neurons. Electron microscopy further reveals accumulation of lipofuscin-like granules in the dorsal root ganglion of Rab18−/− mice. Surprisingly, Rab18 colocalizes, cofractionates, and coprecipitates with the lysosomal regulator Rab7, mutations of which cause Charcot-Marie-Tooth (CMT) neuropathy type 2B. Moreover, Rab7 is upregulated in Rab18-deficient neurons, suggesting a compensatory effect. Together, our results suggest that the functions of RAB18 and RAB7 in lysosomal and autophagic activities may constitute an overlapping mechanism underlying WARBM and CMT pathogenesis in the nervous system.

Keywords

Rab18 Warburg micro syndrome Neuron Axonal degeneration Vesicle trafficking Lysosome Charcot-Marie-Tooth Rab7 Autophagy LC3 

Notes

Acknowledgements

We appreciate Dr. Mu-Ming Poo (University of California, Berkeley), Dr. Chih-Chiang Chan (National Taiwan University), and Ms. Elise Shen (University of Texas, Austin) for helpful comments and suggestions. The authors also wish to thank the Instrumentation Resource Center, National Yang-Ming University, and the National RNAi Core Facility at Academia Sinica, Taiwan for their technical support.

Authors’ Contributions

Study conception and design: JWT, CJH, LSK, MJF, and CYT. Project supervision: JWT. Data collection: FSN, LLL, CYC, PCW, YTL, BSR, and CYT. Data analysis and interpretation: FSN, LLL, JWT, MJF, and LSK. Drafting the article: FSN and JWT. Final approval of the version to be published: all authors.

Funding

This work was supported by the grants of Yen Tjing Ling Medical Foundation (CI-103-4), the Ministry of Science and Technology (NSC 101-2320-B-010-077-MY2, 102-2314-B-075-079, 103-2628-B-010-002-MY3, 104-2633-H-010-001, 104-2745-B-075-001, 105-2633-B-009-003, 106-2321-B-075-001, 106-2628-B-010-002-MY3, and 107-2321-B-075-001), Taipei Veterans General Hospital-University System of Taiwan (VGHUST106-G7-5-2), National Health Research Institutes (NHRI-EX103-10314NC), and Academia Sinica, Taiwan (AS-104-TP-B09 and 2396-105-0100) to JWT; and Taiwan National Science Council (NSC 102-2314-B-075-005-MY3), Taipei Veterans General Hospital (V103E9-004 and V102C-173), and the Ministry of Education Taiwan, Aim for the Top University Plan to CJH. This work is also supported by the Development and Construction Program of NYMU School of Medicine (107F-M01-0502) and the Brain Research Center, NYMU through the Featured Areas Research Center Program within the framework of the Higher Education Sprout Project by the Ministry of Education (MOE), Taiwan.

Compliance with Ethical Standards

Ethical Approval and Consent to Participate

Not applicable.

Consent for Publication

Not applicable.

Competing Interests

The authors declare that they have no competing interests.

Supplementary material

12035_2019_1471_Fig6_ESM.png (328 kb)
Figure S1

Rab18 expression in primary cortical neurons from from Rab18−/− mice. Primary cortical neurons was prepared from E16.5–18.5 embryos of Rab18+/+, Rab18+/- and Rab18−/− mice. Rab18 expression was determined using western blotting. Error bar represent mean ± SEM; n = 2. (PNG 328 kb)

12035_2019_1471_MOESM1_ESM.tif (506 kb)
High resolution image (TIF 505 kb)
12035_2019_1471_Fig7_ESM.png (2.2 mb)
Figure S2

Rab18-associated vesicles are actively transported in PC12 cells. (A) A NGF-differentiated PC12 cell expressing EGFP-Rab18. Rab18 was distributed in vesicle-like structures along the neurite. Scale bar: 10 μm. The dashed box indicated the region of (B) and (C). (B) Time-lapse imaging of vesicle transport. Arrow indicated a Rab18-associated vesicle moving in retrograde direction. Time was indicated in minute:second. (C) The kymograph constructed from individual time-lapse images of the region in (B) through time. Dashed line arrows indicated Rab18-associated vesicles moving in different directions. Scale bar: 5 μm. (PNG 2292 kb)

12035_2019_1471_MOESM2_ESM.tif (4.1 mb)
High resolution image (TIF 4227 kb)
12035_2019_1471_Fig8_ESM.png (648 kb)
Figure S3

Knockdown of Rab18 expression in primary cortical neurons using shRNA. Mouse cortical neuronal culture was infected with lentivirus encoding Rab18 shRNA or control sequence (shCtrl). Two Rab18 shRNA sequences (shRab18–1981, shRab18–7028) targeting different Rab18 mRNA regions effectively knocked down Rab18 expression 5 days after infection. Error bar represent mean ± SEM; n = 7. (PNG 647 kb)

12035_2019_1471_MOESM3_ESM.tif (914 kb)
High resolution image (TIF 914 kb)
12035_2019_1471_MOESM4_ESM.avi (2.4 mb)
Supplementary Video 1 Rab18-associated vesicles transported bi-directionally within the neurite of cultured neurons (AVI 2503 kb)
12035_2019_1471_MOESM5_ESM.avi (3.5 mb)
Supplementary Video 2 Rab18-associated vesicles transported bi-directionally within the neurite of PC12 cells (AVI 3590 kb)
12035_2019_1471_MOESM6_ESM.avi (3 mb)
Supplementary Video 3 Lysosomal trafficking in wild type neurons. (AVI 3088 kb)
12035_2019_1471_MOESM7_ESM.avi (2.6 mb)
Supplementary Video 4 Lysosomal trafficking in Rab18−/− neurons. (AVI 2697 kb)

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Copyright information

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Authors and Affiliations

  • Fang-Shin Nian
    • 1
    • 2
  • Lei-Li Li
    • 1
  • Chih-Ya Cheng
    • 3
  • Pei-Chun Wu
    • 4
    • 5
  • You-Tai Lin
    • 4
  • Cheng-Yung Tang
    • 4
  • Bo-Shiun Ren
    • 1
  • Chin-Yin Tai
    • 6
  • Ming-Ji Fann
    • 4
    • 5
  • Lung-Sen Kao
    • 4
    • 5
  • Chen-Jee Hong
    • 5
    • 7
    • 8
  • Jin-Wu Tsai
    • 1
    • 5
    • 9
    Email author
  1. 1.Institute of Brain ScienceNational Yang-Ming UniversityTaipeiTaiwan
  2. 2.Program in Molecular MedicineNational Yang-Ming University and Academia SinicaTaipeiTaiwan
  3. 3.Department of PediatricsTaipei Veterans General HospitalTaipeiTaiwan
  4. 4.Department of Life Sciences and Institute of Genome SciencesNational Yang-Ming UniversityTaipeiTaiwan
  5. 5.Brain Research CenterNational Yang-Ming UniversityTaipeiTaiwan
  6. 6.Institute of Molecular BiologyAcademia SinicaTaipeiTaiwan
  7. 7.Division of Psychiatry, School of MedicineNational Yang-Ming UniversityTaipeiTaiwan
  8. 8.Department of PsychiatryTaipei Veterans General HospitalTaipeiTaiwan
  9. 9.Biopotonics and Molecular Imaging Research CenterNational Yang-Ming UniversityTaipeiTaiwan

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