Parvalbumin overexpression alters immune-mediated increases in intracellular calcium, and delays disease onset in a transgenic model of familial amyotrophic lateral sclerosis.
Intracellular calcium is increased in vulnerable spinal motoneurons in immune-mediated as well as transgenic models of amyotrophic lateral sclerosis (ALS). To determine whether intracellular calcium levels are influenced by the calcium-binding protein parvalbumin, we developed transgenic mice overexpressing parvalbumin in spinal motoneurons. ALS immunoglobulins increased intracellular calcium and spontaneous transmitter release at motoneuron terminals in control animals, but not in parvalbumin overexpressing transgenic mice. Parvalbumin transgenic mice interbred with mutant SOD1 (mSOD1) transgenic mice, an animal model of familial ALS, had significantly reduced motoneuron loss, and had delayed disease onset (17%) and prolonged survival (11%) when compared with mice with only the mSOD1 transgene. These results affirm the importance of the calcium binding protein parvalbumin in altering calcium homeostasis in motoneurons. The increased motoneuron parvalbumin can significantly attenuate the immune-mediated increases in calcium and to a lesser extent compensate for the mSOD1-mediated 'toxic-gain-of-function' in transgenic mice.
Beers
D R
DR
Ronny and Linda Finger MDA/ALS Research Center, Department of Neurology, Baylor College of Medicine, Houston, Texas 77030, USA.
Ho
B K
BK
Siklós
L
L
Alexianu
M E
ME
Mosier
D R
DR
Mohamed
A H
AH
Otsuka
Y
Y
Kozovska
M E
ME
McAlhany
R E
RE
Smith
R G
RG
Appel
S H
SH
D017668:Age of Onset; D000690:Amyotrophic Lateral Sclerosis / Q000276:immunology / Q000378:metabolism* / Q000401:mortality; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002470:Cell Survival / Q000502:physiology; D002490:Central Nervous System / Q000378:metabolism; D004195:Disease Models, Animal; D015870:Gene Expression / Q000502:physiology; D007107:Immune System / Q000378:metabolism*; D008564:Membrane Potentials / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000166:cytology / Q000502:physiology; D010320:Parvalbumins / Q000235:genetics* / Q000276:immunology; D012333:RNA, Messenger / Q000032:analysis; D013482:Superoxide Dismutase / Q000235:genetics*; D000072105:Superoxide Dismutase-1; D015996:Survival Rate; D019076:Transgenes
D010320:Parvalbumins; D012333:RNA, Messenger; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D002118:Calcium