Disease Progression in a Transgenic Model of Familial Amyotrophic Lateral Sclerosis Is Dependent on Both Neuronal and Non-Neuronal Zinc Binding Proteins

Abstract

Mutations in the Cu/Zn superoxide dismutase (SOD1) gene cause one form of familial amyotrophic lateral sclerosis, a progressive disorder of motor neurons leading to weakness and death of affected individuals. Experiments using both transgenic mice expressing mutant SOD1 and SOD1 knock-out mice have demonstrated that disease is caused by a toxic gain of function and not by a loss of normal SOD1 activity. Precise mechanisms underlying mutant SOD1 toxicity are unclear but may involve abnormal interactions between zinc and SOD1. The metallothioneins (MTs) represent a family of zinc binding proteins that can function as zinc chaperones for apo-SOD1 in vitro. We hypothesized that manipulation of metallothioneins in vivo might alter the disease phenotype of transgenic mice expressing G93A SOD1 and therefore crossed this line with MT-I and MT-II or MT-III knock-out mice. G93A SOD1 mice deficient of either MT-I and MT-II or MT-III exhibited significant reductions in survival compared with G93A SOD1 mice. In addition, motor dysfunction was markedly accelerated in G93A SOD1 mice deficient in metallothioneins with regard to onset (MT-I and MT-II) or progression (MT-III). These results indicate that the disease course in G93A SOD1 mice is dependent on levels of metallothionein expression. Because MT-I and MT-II are expressed in glia whereas MT-III is found in neurons, these results also indicate that primary changes within non-neuronal cells can affect mutant SOD1-induced disease and do so in ways distinct from primary neuronal changes.

Proteasome inhibition induces selective motor neuron death in organotypic slice cultures

“…There is another interesting study about proteasome inhibition using mice spinal (Puttaparthi et al 2003). In the present study, no visible aggregate \vas seen neither in the ubiquitin-nor SODl immunohistochemistry (data not shown).…”

The G59S Mutation in p150gluedCauses Dysfunction of Dynactin in Mice

“…Wild-type and Dctn1 ϩ/m mice showed no significant differences in performance in either the accelerating rotarod or grip strength at 10 and 16 months of age (data not shown). Because older patients carrying the G59S mutation in p150 glued had steppage gait (Puls et al, 2005), and SOD1 G93A mice, a well established mouse model for ALS, developed significantly shorter stride length (Gurney et al, 1994;Puttaparthi et al, 2002;Puls et al, 2005), we examined the gait of Dctn1 ϩ/m mice using the Treadscan Gait Analysis system. We quantified the stride length of wild-type and Dctn1 ϩ/m mice at 4 and 16 months of age.…”

Metallothioneins and brain injury: What transgenic mice tell us

“…Thus, significant upregulation of these proteins has been observed in a number of human neurological diseases, including Alzheimer's disease (55,(79)(80)(81)(82)), Pick's disease (79), short-course Creutzfeld-Jakob disease (72), amyotrophic lateral sclerosis (83)(84)(85), and multiple sclerosis (86,87). Experiments carried out in animal models fully demonstrated the response of MT-1&2 to brain damage elicited by inflammatory factors such as lipopolysaccharides (11, 15, 24, 88), stress (62,(89)(90)(91), glutamate analogues (37,51,59,(92)(93)(94)(95), cryogenic injury (28,32,66,71), stroke/ischemia (17, [95][96][97][98], familial amyotrophic lateral sclerosis models (38,67,99,100), multiple sclerosis models (101)(102)(103), and gliotoxins (104)(105)(106).…”