SorLA in Glia: Shared Subcellular Distribution Patterns with Caveolin-1
SorLA is an established sorting and trafficking protein in neurons with demonstrated relevance to Alzheimer’s disease (AD). It shares these roles with the caveolins, markers of membrane rafts microdomains. To further our knowledge on sorLA’s expression and traffic, we studied sorLA expression in various cultured glia and its relation to caveolin-1 (cav-1), a caveolar microdomain marker. RT-PCR and immunoblots demonstrated sorLA expression in rat C6 glioma, primary cultures of rat astrocytes (PCRA), and human astrocytoma 1321N1 cells. PCRA were determined to express the highest levels of sorLA’s message. Induction of differentiation of C6 cells into an astrocyte-like phenotype led to a significant decrease in sorLA’s mRNA and protein expression. A set of complementary experimental approaches establish that sorLA and cav-1 directly or indirectly interact in glia: (1) co-fractionation in light-density membrane raft fractions of rat C6 glioma, PCRA, and human 1321N1 astrocytoma cells; (2) a subcellular co-localization distribution pattern in vesicular perinuclear compartments seen via confocal imaging in C6 and PCRA; (3) additional confocal analysis in C6 cells suggesting that the perinuclear compartments correspond to their co-localization in early endosomes and the trans-Golgi; and; (4) co-immunoprecipitation data strongly supporting their direct or indirect physical interaction. These findings further establish that sorLA is expressed in glia and that it shares its subcellular distribution pattern with cav-1. A direct or indirect cav-1/sorLA interaction could modify the trafficking and sorting functions of sorLA in glia and its proposed neuroprotective role in AD.
KeywordsAlzheimer’s disease Caveolae Glia Early endosome Trans-Golgi network
This study was supported in part by the NIH-MBRS-SCORE grant S06-GM08224 awarded to WIS, and RCMI Program G12RR03051 at UPR-MSC. Graduate students IKS, JOG, and NAM were supported by the NIGMS-MBRS-RISE grant GM61838 at UPR-MSC. The authors are also grateful to Mr. Bismarck Madera for his valuable assistance with the LSCM studies.
- Andersen OM, Reiche J, Schmidt V, Gotthardt M, Spoelgen R, Behlke J, von Arnim CA, Breiderhoff T, Jansen P, Wu X, Bales KR, Cappai R, Masters CL, Gliemann J, Mufson EJ, Hyman BT, Paul SM, Nykjaer A, Willnow TE (2005) Neuronal sorting protein-related receptor sorLA/LR11 regulates processing of the amyloid precursor protein. Proc Natl Acad Sci 102:13461–13466PubMedCrossRefGoogle Scholar
- Kölsch H, Jessen F, Wiltfang J, Lewczuk P, Dichgans M, Teipel SJ, Kornhuber J, Frölich L, Heuser I, Peters O, Wiese B, Kaduszkiewicz H, van den Bussche H, Hüll M, Kurz A, Rüther E, Henn FA, Maier W (2009) Association of SORL1 gene variants with Alzheimer’s disease. Brain Res 1264:1–6PubMedCrossRefGoogle Scholar
- Lackland J., Dreyfus CF (2002) Trophins as mediators of astrocytes effects in the aging and regenerating brain. In De Vellis JS (ed) Neuroglia in the aging brain, 1st edn. Human Press, Totowa, pp 199–216Google Scholar
- Rajendran L, Simons K (2009) Membrane trafficking and targeting in Alzheimer’s disease. In St George-Hyslop P et al (eds) Intracellular traffic and neurodegenerative disorders, research and perspectives in Alzheimer’s Disease, Springer, Heidelberg, pp 103–113Google Scholar
- Rogaeva E, Meng Y, Lee JH, Mayeux R, Farrer LA, St George-Hyslop P (2009) The sortilin-related receptor SORL1 is functionally and genetically associated with Alzheimer’s Disease. In St George-Hyslop P et al (eds) Intracellular traffic and neurodegenerative disorders, research and perspectives in Alzheimer’s Disease. Springer, BerlinGoogle Scholar
- Rohe M, Synowitz M, Glass R, Paul SM, Paul SM, Nykjaer A, Willnow TE (2009) Brain-derived neurotrophic factor reduces amyloidogenc processing through control of sorLA gene expression. J Neurosci 29(49):15472–15478Google Scholar
- Yamazaki H, Bujo H, Kusunoki J, Seimiya K, Kanaki T, Morisaki N, Schneider WJ, Saito Y (1996) Elements of neural adhesion molecules and a yeast vacuolar protein sorting receptor are present in a novel mammalian low-density lipoprotein receptor family member. J Biol Chem 271:24761–24768PubMedCrossRefGoogle Scholar