Parvalbumin overexpression alters immune‐mediated increases in intracellular calcium, and delays disease onset in a transgenic model of familial amyotrophic lateral sclerosis

Abstract

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 in¯uenced by the calciumbinding 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 signi®cantly reduced motoneuron loss, and had delayed disease onset (17%) and prolonged survival (11%) when compared with mice with only the mSOD1 transgene. These results af®rm the importance of the calcium binding protein parvalbumin in altering calcium homeostasis in motoneurons. The increased motoneuron parvalbumin can signi®-cantly attenuate the immune-mediated increases in calcium and to a lesser extent compensate for the mSOD1-mediated toxic-gain-of-function' in transgenic mice.

Intracellular Ca2+Regulates Free-Running Circadian Clock OscillationIn Vivo

“…This indicates that PV is an effective tool for modifying the dynamics of intracellular Ca 2ϩ signals in transgenic fly neurons without nonspecifically harming them or abolishing synaptic communication. Indeed, PV has been used in transgenic mice as a protective agent that prevents cytotoxicity and neuronal cell death in the following contexts: a transgenic model of amyotrophic lateral sclerosis, pharmacologically induced excitotoxicity, and physical injury to motoneurons (Beers et al, 2001;Van Den Bosch et al, 2002;Dekkers et al, 2004).…”

Glutamate pathway implication in amyotrophic lateral sclerosis: what is the signal in the noise?

“…176,225 Transgenic mice overexpressing parvalbumin in spinal MNs were interbred with mutant SOD1 mice and exhibited a ∼17% delayed onset of motor defects and an ∼11% prolonged survival. 226 However, the marginal survival extension in this double transgenic mouse implies that other mechanisms associated or not with intracellular Ca 2+ are taking place in ALS pathogenesis.…”

Morphologic and neurochemical alterations in the superior colliculus of the genetically epilepsy-prone hamster (GPG/Vall)

“…Accordingly, increased levels of parvalbumin immunostaining in the IC and also in its afferent sources have been observed in the GPG/Vall hamster (Fuentes-Santamaria et al, 2005a). This upregulation may be the result of an attempt to attenuate degeneration and therefore improve cell survival (Beers et al, 2001). Thus, it is possible that the significant decrease in the parvalbumin immunostained neuropil observed in the SC of the GPG/Vall hamster indicates an atrophy of neuronal processes such as dendrites while the significant increase in the mean gray level within parvalbumin immunostained neurons represents a neuroprotective effect against calcium overload associated with epileptic seizures (Kamphuis et al, 1989;Fabene et al, 2001).…”