Effects of ALS-related SOD1 mutants on dynein- and KIF5-mediated retrograde and anterograde axonal transport

Department of Molecular and Cellular Biochemistry, College of Medicine, University of Kentucky, Lexington, KY 40536, USA.
Biochimica et Biophysica Acta (Impact Factor: 4.66). 09/2010; 1802(9):707-16. DOI: 10.1016/j.bbadis.2010.05.008
Source: PubMed


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.

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    • "Cumulative evidence indicates mitochondrial dysfunction, impaired transport, altered dynamics, and perturbation of mitochondrial turnover are associated with the pathology of major neurodegenerative disorders (Chen and Chan, 2009; Sheng and Cai, 2012). Defective mitochondrial transport accompanied by mitochondrial pathology is one of the most notable pathological changes in several aging-associated neurodegenerative diseases, including Alzheimer's disease (Rui et al., 2006; Du et al., 2010; Calkins et al., 2011) and amyotrophic lateral sclerosis (De Vos et al., 2007; Magrané and Manfredi, 2009; Bilsland et al., 2010; Shi et al., 2010; Martin, 2011; Zhu and Sheng, 2011; Marinkovic et al., 2012). Dysfunctional mitochondria not only supply less ATP and maintain Ca 2+ buffering capacity less efficiently, but also release harmful reactive oxygen species (ROS). "
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    ABSTRACT: Mitochondria are essential organelles for neuronal growth, survival, and function. Neurons use specialized mechanisms to drive mitochondria transport and to anchor them in axons and at synapses. Stationary mitochondria buffer intracellular Ca(2+) and serve as a local energy source by supplying ATP. The balance between motile and stationary mitochondria responds quickly to changes in axonal and synaptic physiology. Defects in mitochondrial transport are implicated in the pathogenesis of several major neurological disorders. Recent work has provided new insight in the regulation of microtubule-based mitochondrial trafficking and anchoring, and on how mitochondrial motility influences neuron growth, synaptic function, and mitophagy.
    The Journal of Cell Biology 03/2014; 204(7):1087-98. DOI:10.1083/jcb.201312123 · 9.83 Impact Factor
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    • "The selective effect of mSOD1 on anterograde, but not retrograde FAT in isolated axoplasm was unexpected, given reports describing inhibition of both anterograde and retrograde FAT in G93A-SOD1 mice [14], [28], [53], [54]. Some reports were based on reduced accumulation of FAT membrane proteins at a nerve ligation [14], [54]. "
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    ABSTRACT: Dying-back degeneration of motor neuron axons represents an established feature of familial amyotrophic lateral sclerosis (FALS) associated with superoxide dismutase 1 (SOD1) mutations, but axon-autonomous effects of pathogenic SOD1 remained undefined. Characteristics of motor neurons affected in FALS include abnormal kinase activation, aberrant neurofilament phosphorylation, and fast axonal transport (FAT) deficits, but functional relationships among these pathogenic events were unclear. Experiments in isolated squid axoplasm reveal that FALS-related SOD1 mutant polypeptides inhibit FAT through a mechanism involving a p38 mitogen activated protein kinase pathway. Mutant SOD1 activated neuronal p38 in mouse spinal cord, neuroblastoma cells and squid axoplasm. Active p38 MAP kinase phosphorylated kinesin-1, and this phosphorylation event inhibited kinesin-1. Finally, vesicle motility assays revealed previously unrecognized, isoform-specific effects of p38 on FAT. Axon-autonomous activation of the p38 pathway represents a novel gain of toxic function for FALS-linked SOD1 proteins consistent with the dying-back pattern of neurodegeneration characteristic of ALS.
    PLoS ONE 06/2013; 8(6):e65235. DOI:10.1371/journal.pone.0065235 · 3.23 Impact Factor
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    • "The pathological mechanism underlying this mutant is the disruption of KIF5A’s ability to bind with microtubules, leading to a failure of adequate anterograde transport [26]. Because KIF5A motor proteins transport many cargos that are important for neurons, including neurofilaments, mitochondria, and SNARE proteins essential for synaptic vesicle docking [27,28], disruption of KIF5A motility results in dysregulation of axonal homeostasis. In addition to mutations in the kinesin family itself, modifications of the motor domain are also potential causes of MNDs [29]. "
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    ABSTRACT: Motor neurons typically have very long axons, and fine-tuning axonal transport is crucial for their survival. The obstruction of axonal transport is gaining attention as a cause of neuronal dysfunction in a variety of neurodegenerative motor neuron diseases. Depletions in dynein and dynactin-1, motor molecules regulating axonal trafficking, disrupt axonal transport in flies, and mutations in their genes cause motor neuron degeneration in humans and rodents. Axonal transport defects are among the early molecular events leading to neurodegeneration in mouse models of amyotrophic lateral sclerosis (ALS). Gene expression profiles indicate that dynactin-1 mRNA is downregulated in degenerating spinal motor neurons of autopsied patients with sporadic ALS. Dynactin-1 mRNA is also reduced in the affected neurons of a mouse model of spinal and bulbar muscular atrophy, a motor neuron disease caused by triplet CAG repeat expansion in the gene encoding the androgen receptor. Pathogenic androgen receptor proteins also inhibit kinesin-1 microtubule-binding activity and disrupt anterograde axonal transport by activating c-Jun N-terminal kinase. Disruption of axonal transport also underlies the pathogenesis of spinal muscular atrophy and hereditary spastic paraplegias. These observations suggest that the impairment of axonal transport is a key event in the pathological processes of motor neuron degeneration and an important target of therapy development for motor neuron diseases.
    International Journal of Molecular Sciences 12/2012; 13(1):1225-38. DOI:10.3390/ijms13011225 · 2.86 Impact Factor
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