Potential role(s) of the dynein-dynactin motor complex in mutant
SOD1-mediated ALS. Dynein-dynactin can sequester and transport mutant SOD1
to form large aggresome-like inclusions that require autophagic degradation.
Dynein is also involved in the autophagosome-lysosome fusion that is critical
to the degradation of misfolded protein inclusions in autophagosomes.
Interplay of the two dynein-dependent events, the formation and degradation of
inclusions, determines the eventual inclusion burden in neurons. Increased
levels of mutant SOD1 associated with dynein as the disease progresses could
contribute to decreased axonal transport in ALS by multiple mechanisms. These
potential mechanisms illustrated here include competitive occupancy of the
dynein-mediated transport capacity, disruption of dynein motor activity,
destabilization of microtubules, physical blockage of transport by mutant SOD1
aggregates in the axon. Decreased retrograde transport of cargos such as
mitochondria and neurotrophic factors as well as increased aggregation burden
may determine the toxicity of mutant SOD1 and ALS disease manifestation.