Axonal Transport in Animal models of Amyotrophic Lateral Sclerosis

The work in this PhD thesis was focused on the motor neuron disease ALS, because – in my view – the question if and how transport impairments are involved in ALS pathogenesis is still not settled. By imaging changes in axonal morphology and organelle transport over time in several animal models of ALS, I found that deficits in axonal transport of organelles (mitochondria and endosomes) and axon degeneration can evolve independently. This conclusion rests on the following results: (I) Axons can survive despite long-lasting transport deficits: In the SODG93A model of ALS, transport deficits are detected soon after birth, months before the onset of axon degeneration. (II) Transport deficits are not necessary for axon degeneration: In the SODG85R model of ALS, motor axons degenerate, but transport is unaffected. (III) Axon transport deficits are not sufficient to cause degeneration: In mice that over-express wild-type superoxide dismutase-1 (SODWT), axons show chronic transport deficits, but survive. Taken together these findings indicate that transport deficits are neither necessary nor sufficient to cause axon degeneration in these classical ALS models.