The long haul: microtubule motors as the essential supply line for neuronal longevity

The extreme morphology and polarised architecture of neurons require the highly sophisticated microtubule transport system for both construction and lifelong survival. Genomic evidence from an expanding landscape of human mutations supports the essential role of the microtubule transport machinery. During neurodevelopment, mutations disrupt the proliferation and migration of neuronal precursors, as well as the initial establishment of polarity. In the mature nervous system, the reliance on microtubule transport shifts to the long-term maintenance of axon integrity and synaptic proteostasis. Across the motor proteins responsible for long distance transport in neurons, mutations highlight a specific vulnerability of long axons to transport failure in Hereditary Spastic Paraplegia (HSP), Charcot Marie Tooth disease Type 2 (CMT2), Spinal Muscular Atrophy (SMA), Perry Syndrome, and Amyotrophic Lateral Sclerosis (ALS) amongst others. Due to the role of microtubule motors in development and maintenance, there is frequently a phenotypic spectrum within a single gene of the microtubule transport system. For example, mutations in dynein motors are linked both to malformations of cortical development and specific motor neuron loss in SMA-LED (Spinal Muscular Atrophy with Lower Extremity Predominance). By synthesising genetic evidence, this review illustrates how specific molecular failures, ranging from motor-domain kinetics to cargo binding, can inform our understanding of neuronal homeostasis. Ultimately, we argue that microtubule transport is not merely a cellular utility, but a key determinant of neuronal longevity.