Mice with Mutation in Dynein Heavy Chain 1 Do Not Share the Same Tau Expression Pattern with Mice with SOD1-Related Motor Neuron Disease

Abstract

Due to controversy about the involvement of Dync1h1 mutation in pathogenesis of motor neuron disease, we investigated expression of tau protein in transgenic hybrid mice with Dync1h1 (so-called Cra1/+), SOD1G93A (SOD1/+), double (Cra1/SOD1) mutations and wild-type controls. Total tau-mRNA and isoforms 0, 1 and 2 N expression was studied in frontal cortex, hippocampus, spinal cord and cerebellum of presymptomatic and symptomatic animals (age 70, 140 and 365 days). The most significant differences were found in brain cortex and cerebellum, but not in hippocampus and spinal cord. There were less changes in Cra1/SOD1 double heterozygotes compared to mice harboring single mutations. The differences in total tau expression and in profile of its isoforms between Cra1/+ and SOD1/+ transgenics indicate a distinct pathogenic entity of these two conditions.

Kinesin Expression in the Central Nervous System of Humans and Transgenic hSOD1G93A<b> </b>Mice with Amyotrophic Lateral Sclerosis

“…In mice, among the CNS parts studied, the most visible changes were seen in the frontal brain cortex, where the expression of all kinesins at the symptomatic stage was 45-85% higher than in wild-type controls. In the same structure, as we have shown earlier, the total tau expression was decreased by more than 60% at the symptomatic stage [28], and similarly to kinesins, it was unchanged at the presymptomatic stage. Tau participates in polymerization, stabilization and organization of microtubules, tracts on which kinesins move their cargos [31,32].…”

“…However, many fundamental aspects of intracellular transport including the interactions between microtubule-associated proteins and motor proteins or links between cargo carriers and the occurrence of clinical symptoms remain poorly understood. In our earlier studies conducted on transgenic mice with symptoms of motor neuron degeneration (so-called SOD1, with human SOD1G93A mutation and Cra1, with Dync1h1 mutation), we observed changes in tau, one of the microtubule-associated proteins, alternative splicing and a significant decrease in total tau expression especially in SOD1 mice [28]. Since it is known that tau inhibits kinesin activity [29,30], we continued the studies on the same mouse strain with the human SOD1G93A mutation (model for FALS) and determined the expression of selected kinesins, specific for the CNS.…”

“…The N-terminal part of tau is also crucial for the determination of spacing between microtubules [33,34]. As we have shown, the N-terminal but not the C-terminal part of tau is affected in the SOD1G93A mice [28,35]. LaPointe et al [36] indicated that the first 18 amino acids at the N terminus of squid axoplasm tau are required to elicit the inhibitory effect of tau filaments on kinesin-dependent fast axonal anterograde transport.…”

“…For this reason, the tau accumulation in Alzheimer's disease may severely compromise kinesin-driven anterograde transport leading to neurodegeneration [30]. However, the situation in SOD1-mediated ALS seems to be different, since the level of tau decreases in the frontal cortex much below its normal value [28] and kinesin expression increases dramatically. Increased expression of kinesins involved in anterograde (KIF5A and 5C) but also in retrograde (KIFC2) axonal transport, observed in the frontal cortex of symptomatic mice, may be a part of the cell adaptation process to decreased tau expression (its N-terminal part) and subsequent disturbance in the structure of microtubules (tracts for kinesins).…”

“…However, growing evidence indicates the presence of functional changes in this structure in the course of ALS, including increased activations of areas involved in motor learning, among which basal ganglia and the cerebellum [38]. In our earlier studies of tau mRNA expressions in the cerebellum of SOD1G93A mice, we observed its very high increase at both presymptomatic and symptomatic stages, which was an opposite finding compared to the changes observed in the frontal cortex and spinal cord, the structures stereotypically involved in ALS pathogenesis [28,39]. It is possible that the kinesin expression is downregulated in response to increased tau expression.…”