Transport of organelles, vesicles and macromolecules by microtubule-based motors is critical for cellular organisation. Due to their extended processes, neurons are particularly reliant on these trafficking processes occurring efficiently. This fact is underlined by the discovery that mutations in motor proteins and their co-factors cause neurodevelopmental and age-related neurodegenerative disorders. Defective axonal transport has also been observed in neurodegenerative diseases caused by other mutations, although whether this a cause or consequence of the pathology is actively debated.

The overarching goal of our group is to understand how microtubule motors traffic their cargoes to distinct sites within cells, and the connections between defective transport processes and neuronal dysfunction during ageing and disease. We address these problems by
combining reconstitution of transport complexes in vitro with genetic dissection of cargo trafficking in Drosophila and mammalian cells. In this seminar, I will review our work using Drosophila to elucidate the function and regulation of axonal transport during ageing. I will then present evidence from iPS cell-derived neurons and single-molecule imaging that inhibitory interactions with the transport machinery contribute directly to the most common familial form of amyotrophic lateral sclerosis.