Transport of material and signals between extensive neuronal processes and the cell body is essential to neuronal physiology and survival. Slowing of axonal transport has been shown to occur before the onset of symptoms in amyotrophic lateral sclerosis (ALS). We have previously shown that several familial ALS-linked copper-zinc superoxide dismutase (SOD1) mutants (A4V, G85R, and G93A) interacted and colocalized with the retrograde dynein-dynactin motor complex in cultured cells and affected tissues of ALS mice. We also found that the interaction between mutant SOD1 and the dynein motor played a critical role in the formation of large inclusions containing mutant SOD1. In this study, we showed that, in contrast to the dynein situation, mutant SOD1 did not interact with anterograde transport motors of the kinesin-1 family (KIF5A, B and C). Using dynein and kinesin accumulation at the sciatic nerve ligation sites as a surrogate measurement of axonal transport, we also showed that dynein mediated retrograde transport was slower in G93A than in WT mice at an early presymptomatic stage. While no decrease in KIF5A-mediated anterograde transport was detected, the slowing of anterograde transport of dynein heavy chain as a cargo was observed in the presymptomatic G93A mice. The results from this study along with other recently published work support that mutant SOD1 might only interact with and interfere with some kinesin members, which, in turn, could result in the impairment of a selective subset of cargos. Although it remains to be further investigated how mutant SOD1 affects different axonal transport motor proteins and various cargos, it is evident that mutant SOD1 can induce defects in axonal transport, which, subsequently, contribute to the propagation of toxic effects and ultimately motor neuron death in ALS.
|Number of pages||10|
|Journal||Biochimica et Biophysica Acta - Molecular Basis of Disease|
|State||Published - Sep 2010|
Bibliographical noteFunding Information:
We are grateful to Dr. Xiaojiang Li at Emory University for providing the pcDNA3-rKLC2 plasmid and to Dr. Scott Brady at University of Illinois at Chicago for providing the KLC antibody. Mrs. Li Liu is acknowledged for assistance with animal studies. This study was in part supported by the NIH grants R01NS049126 and R21AG032567 to HZ.
- Amyotrophic lateral sclerosis
- Axonal transport
- Copper-zinc superoxide dismutase
ASJC Scopus subject areas
- Molecular Medicine
- Molecular Biology