Impaired αGDI Function in the X-Linked Intellectual Disability: The Impact on Astroglia Vesicle Dynamics

Overview

Journal Mol Neurobiol

Specialties Molecular Biology
Neurology

Date 2016 Mar 14

PMID 26971292

Citations 6

Authors

Maja Potokar

Jernej Jorgacevski

Valentina Lacovich

Marko Kreft

Nina Vardjan

Veronica Bianchi

Patrizia DAdamo

Robert Zorec

Affiliations

Soon will be listed here.

Abstract

X-linked non-syndromic intellectual disability (XLID) is a common mental disorder recognized by cognitive and behavioral deficits. Mutations in the brain-specific αGDI, shown to alter a subset of RAB GTPases redistribution in cells, are linked to XLID, likely via changes in vesicle traffic in neurons. Here, we show directly that isolated XLID mice astrocytes, devoid of pathologic tissue environment, exhibit vesicle mobility deficits. Contrary to previous studies, we show that astrocytes express two GDI proteins. The siRNA-mediated suppression of expression of αGDI especially affected vesicle dynamics. A similar defect was recorded in astrocytes from the Gdi1 mouse model of XLID and in astrocytes with recombinant mutated human XLID αGDI. Endolysosomal vesicles studied here are involved in the release of gliosignaling molecules as well as in regulating membrane receptor density; thus, the observed changes in astrocytic vesicle mobility may, over the long time-course, profoundly affect signaling capacity of these cells, which optimize neural activity.

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References

Lai C, Xie C, Shim H, Chandran J, Howell B, Cai H . Regulation of endosomal motility and degradation by amyotrophic lateral sclerosis 2/alsin. Mol Brain. 2009; 2:23. PMC: 2724476. DOI: 10.1186/1756-6606-2-23. View

Zerial M, McBride H . Rab proteins as membrane organizers. Nat Rev Mol Cell Biol. 2001; 2(2):107-17. DOI: 10.1038/35052055. View

Schutz G, Axmann M, Freudenthaler S, Schindler H, Kandror K, Roder J . Visualization of vesicle transport along and between distinct pathways in neurites of living cells. Microsc Res Tech. 2004; 63(3):159-67. DOI: 10.1002/jemt.20016. View

McCaffrey M, Bielli A, Cantalupo G, Mora S, Roberti V, Santillo M . Rab4 affects both recycling and degradative endosomal trafficking. FEBS Lett. 2001; 495(1-2):21-30. DOI: 10.1016/s0014-5793(01)02359-6. View

Pangrsic T, Potokar M, Stenovec M, Kreft M, Fabbretti E, Nistri A . Exocytotic release of ATP from cultured astrocytes. J Biol Chem. 2007; 282(39):28749-28758. DOI: 10.1074/jbc.M700290200. View

Parpura V, Baker B, Jeras M, Zorec R . Regulated exocytosis in astrocytic signal integration. Neurochem Int. 2010; 57(4):451-9. PMC: 2892557. DOI: 10.1016/j.neuint.2010.02.007. View

Parpura V, Zorec R . Gliotransmission: Exocytotic release from astrocytes. Brain Res Rev. 2009; 63(1-2):83-92. PMC: 2862866. DOI: 10.1016/j.brainresrev.2009.11.008. View

Nishimura N, Nakamura H, Takai Y, Sano K . Molecular cloning and characterization of two rab GDI species from rat brain: brain-specific and ubiquitous types. J Biol Chem. 1994; 269(19):14191-8. View

Stenovec M, Kreft M, Grilc S, Potokar M, Kreft M, Pangrsic T . Ca2+-dependent mobility of vesicles capturing anti-VGLUT1 antibodies. Exp Cell Res. 2007; 313(18):3809-18. DOI: 10.1016/j.yexcr.2007.08.020. View

10.

Pangrsic T, Potokar M, Haydon P, Zorec R, Kreft M . Astrocyte swelling leads to membrane unfolding, not membrane insertion. J Neurochem. 2006; 99(2):514-23. DOI: 10.1111/j.1471-4159.2006.04042.x. View

11.

Potokar M, Stenovec M, Kreft M, Gabrijel M, Zorec R . Physiopathologic dynamics of vesicle traffic in astrocytes. Histol Histopathol. 2010; 26(2):277-84. DOI: 10.14670/HH-26.277. View

12.

Ropers H . X-linked mental retardation: many genes for a complex disorder. Curr Opin Genet Dev. 2006; 16(3):260-9. DOI: 10.1016/j.gde.2006.04.017. View

13.

Nedergaard M, Ransom B, Goldman S . New roles for astrocytes: redefining the functional architecture of the brain. Trends Neurosci. 2003; 26(10):523-30. DOI: 10.1016/j.tins.2003.08.008. View

14.

DAdamo P, Welzl H, Papadimitriou S, di Barletta M, Tiveron C, Tatangelo L . Deletion of the mental retardation gene Gdi1 impairs associative memory and alters social behavior in mice. Hum Mol Genet. 2002; 11(21):2567-80. DOI: 10.1093/hmg/11.21.2567. View

15.

Jordens I, Marsman M, Kuijl C, Neefjes J . Rab proteins, connecting transport and vesicle fusion. Traffic. 2005; 6(12):1070-7. DOI: 10.1111/j.1600-0854.2005.00336.x. View

16.

Stenovec M, Trkov S, Lasic E, Terzieva S, Kreft M, Arellano J . Expression of familial Alzheimer disease presenilin 1 gene attenuates vesicle traffic and reduces peptide secretion in cultured astrocytes devoid of pathologic tissue environment. Glia. 2015; 64(2):317-29. PMC: 4707995. DOI: 10.1002/glia.22931. View

17.

Verkhratsky A, Parpura V . Astrogliopathology in neurological, neurodevelopmental and psychiatric disorders. Neurobiol Dis. 2015; 85:254-261. PMC: 4592688. DOI: 10.1016/j.nbd.2015.03.025. View

18.

Vardjan N, Verkhratsky A, Zorec R . Pathologic potential of astrocytic vesicle traffic: new targets to treat neurologic diseases?. Cell Transplant. 2015; 24(4):599-612. DOI: 10.3727/096368915X687750. View

19.

Bianchi V, Gambino F, Muzio L, Toniolo D, Humeau Y, DAdamo P . Forebrain deletion of αGDI in adult mice worsens the pre-synaptic deficit at cortico-lateral amygdala synaptic connections. PLoS One. 2012; 7(1):e29763. PMC: 3264564. DOI: 10.1371/journal.pone.0029763. View

20.

Potokar M, Kreft M, Li L, Daniel Andersson J, Pangrsic T, Chowdhury H . Cytoskeleton and vesicle mobility in astrocytes. Traffic. 2007; 8(1):12-20. DOI: 10.1111/j.1600-0854.2006.00509.x. View