title: Neuronal overexpression of IP₃ receptor 2 is detrimental in mutant SOD1 mice.
abstract: Amyotrophic Lateral Sclerosis (ALS) is a devastating neurodegenerative disease causing progressive paralysis of the patient followed by death on average 3-5 years after diagnosis. Disease pathology is multi-factorial including the process of excitotoxicity that induces cell death by cytosolic Ca(2+) overload. In this study, we increased the neuronal expression of an endoplasmic reticulum (ER) Ca(2+) release channel, inositol 1,4,5-trisphosphate receptor 2 (IP(3)R2), to assess whether increased cytosolic Ca(2+) originating from the ER is detrimental for neurons. Overexpression of IP(3)R2 in N2a cells using a Thy1.2-IP(3)R2 construct increases cytosolic Ca(2+) concentrations evoked by bradykinin. In addition, mice generated from this construct have increased expression of IP(3)R2 in the spinal cord and brain. This overexpression of IP(3)R2 does not affect symptom onset, but decreases disease duration and shortens the lifespan of the ALS mice significantly. These data suggest that ER Ca(2+) released by IP(3) receptors may be detrimental in ALS and that motor neurons are vulnerable to impaired Ca(2+) metabolism.
authors.affiliation: Laboratory of Neurobiology and Leuven Research Institute for Neuroscience and Disease (LIND), KU Leuven, Belgium.
authors.forename: Kim A
authors.initials: KA
authors.lastname: Staats
authors.forename: Elke
authors.initials: E
authors.lastname: Bogaert
authors.forename: Nicole
authors.initials: N
authors.lastname: Hersmus
authors.forename: Tom
authors.initials: T
authors.lastname: Jaspers
authors.forename: Tomas
authors.initials: T
authors.lastname: Luyten
authors.forename: Geert
authors.initials: G
authors.lastname: Bultynck
authors.forename: Jan B
authors.initials: JB
authors.lastname: Parys
authors.forename: Chihiro
authors.initials: C
authors.lastname: Hisatsune
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Mikoshiba
authors.forename: Philip
authors.initials: P
authors.lastname: Van Damme
authors.forename: Wim
authors.initials: W
authors.lastname: Robberecht
authors.forename: Ludo
authors.initials: L
authors.lastname: Van Den Bosch
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D004195:Disease Models, Animal; D004721:Endoplasmic Reticulum / Q000378:metabolism; D006801:Humans; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000235:genetics; D000072105:Superoxide Dismutase-1
chemical_list: D053496:Inositol 1,4,5-Trisphosphate Receptors; C000606290:SOD1 protein, human; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1