Fingolimod phosphate inhibits astrocyte inflammatory activity in mucolipidosis IV

Human Molecular Genetics
Laura D WeinstockYulia Grishchuk

Abstract

Mucolipidosis IV (MLIV) is an orphan neurodevelopmental disease that causes severe neurologic dysfunction and loss of vision. Currently there is no therapy for MLIV. It is caused by loss of function of the lysosomal channel mucolipin-1, also known as TRPML1. Knockout of the Mcoln1 gene in a mouse model mirrors clinical and neuropathologic signs in humans. Using this model, we previously observed robust activation of microglia and astrocytes in early symptomatic stages of disease. Here we investigate the consequence of mucolipin-1 loss on astrocyte inflammatory activation in vivo and in vitro and apply a pharmacologic approach to restore Mcoln1-/- astrocyte homeostasis using a clinically approved immunomodulator, fingolimod. We found that Mcoln1-/- mice over-express numerous pro-inflammatory cytokines, some of which were also over-expressed in astrocyte cultures. Changes in the cytokine profile in Mcoln1-/- astrocytes are concomitant with changes in phospho-protein signaling, including activation of PI3K/Akt and MAPK pathways. Fingolimod promotes cytokine homeostasis, down-regulates signaling within the PI3K/Akt and MAPK pathways and restores the lysosomal compartment in Mcoln1-/- astrocytes. These data suggest that fingolimod i...Continue Reading

References

Dec 1, 1991·American Journal of Medical Genetics·D ChitayatS Carpenter
Jul 1, 1982·American Journal of Medical Genetics·B F CrandallD A Bluestone
Aug 26, 1998·Neurology·K P FreiR Schiffmann
Aug 12, 1999·American Journal of Human Genetics·S A SlaugenhauptJ F Gusella
Sep 6, 2000·Nature Genetics·R BargalG Bach
Jul 20, 2002·Current Molecular Medicine·Susan A Slaugenhaupt
Aug 17, 2002·Neurology·G AltarescuR Schiffmann
Dec 1, 2004·Pflügers Archiv : European journal of physiology·Gideon Bach
Dec 8, 2004·Journal of Computational Biology : a Journal of Computational Molecular Cell Biology·Kevin A JanesDouglas A Lauffenburger
Oct 4, 2005·Proceedings of the National Academy of Sciences of the United States of America·Aravind SubramanianJill P Mesirov
Nov 18, 2005·Knee Surgery, Sports Traumatology, Arthroscopy : Official Journal of the ESSKA·Ejnar Eriksson
Apr 1, 2006·Knee Surgery, Sports Traumatology, Arthroscopy : Official Journal of the ESSKA·Ejnar Eriksson
Oct 10, 2007·American Journal of Human Genetics·Bhuvarahamurthy VenugopalSusan A Slaugenhaupt
Jan 20, 2009·Journal of Neuropathology and Experimental Neurology·Matthew C MicsenyiSteven U Walkley
Mar 23, 2010·Cell·Christopher K GlassFred H Gage
Mar 31, 2010·The Journal of Immunology : Official Journal of the American Association of Immunologists·Xiangyu MaHongwei Qin
Jul 6, 2010·Neurobiology of Disease·Cyntia Curcio-MorelliSusan A Slaugenhaupt
Oct 6, 2010·Advances in Experimental Medicine and Biology·Graham M StrubSarah Spiegel
Oct 15, 2010·Journal of Neuroinflammation·Bridgette D SempleM Cristina Morganti-Kossmann
Dec 24, 2010·Proceedings of the National Academy of Sciences of the United States of America·Ji Woong ChoiJerold Chun
Feb 4, 2011·Advances in Experimental Medicine and Biology·Grace A Colletti, Kirill Kiselyov
Jul 19, 2011·Molecular Genetics and Metabolism·Kazuyo WakabayashiEhud Goldin
Jul 25, 2012·Proceedings of the National Academy of Sciences of the United States of America·Chiara Di MaltaAndrea Ballabio
Oct 11, 2012·Autophagy·Chiara Di MaltaAndrea Ballabio
Oct 30, 2012·Bioinformatics·Alexander DobinThomas R Gingeras
Mar 21, 2013·Journal of Neuroinflammation·Celina WuJack P Antel
Sep 10, 2014·Acta Neuropathologica Communications·Yulia GrishchukSusan A Slaugenhaupt
Sep 28, 2014·Bioinformatics·Simon AndersWolfgang Huber
Oct 14, 2014·Frontiers in Cellular Neuroscience·Robert BrunkhorstWaltraud Pfeilschifter
Dec 4, 2014·Journal of Neuropathology and Experimental Neurology·Laura A N PeferoenSandra Amor

❮ Previous
Next ❯

Citations

Jun 18, 2020·International Journal of Molecular Sciences·Kim M A De Kleijn, Gerard J M Martens
Jun 27, 2020·Disease Models & Mechanisms·Molly MepyansKirill Kiselyov
Jan 23, 2021·Orphanet Journal of Rare Diseases·Ayelet VardiAnthony H Futerman
Apr 7, 2021·Human Molecular Genetics·Samantha DeRosaYulia Grishchuk
May 10, 2021·Neuroscience Letters·Albert MiskoYulia Grishchuk
May 12, 2020·Biochimica Et Biophysica Acta. Biomembranes·Marjan Huizing, William A Gahl

❮ Previous
Next ❯

Related Concepts

Related Feeds

Astrocytes

Astrocytes are glial cells that support the blood-brain barrier, facilitate neurotransmission, provide nutrients to neurons, and help repair damaged nervous tissues. Here is the latest research.

Astrocytes & Neurodegeneration

Astrocytes are important for the health and function of the central nervous system. When these cells stop functioning properly, either through gain of function or loss of homeostatic controls, neurodegenerative diseases can occur. Here is the latest research on astrocytes and neurodegeneration.

AKT Pathway

This feed focuses on the AKT serine/threonine kinase, which is an important signaling pathway involved in processes such as glucose metabolism and cell survival.