Hyperactive KIF5A in Neurodegeneration.

Abstract

The highly polarised morphology of neurons and the sheer length of their axons make transport of cargoes throughout the cell a formidable task. Decades of evidence obtained from genetic studies on patients and animal models highlight deficits in axonal transport as a recurrent cause, or early contributing factor, in a plethora of neurodegenerative diseases. Axonal transport abnormalities usually manifest as a slowing of cargo trafficked by molecular motors along microtubules; however, hyperactivation of motors can also lead to disease. That is the case for the kinesin-1 protein KIF5A, in which hyperactive mutations are linked to amyotrophic lateral sclerosis (ALS) and neonatal intractable myoclonus (NEIMY). In this Perspective, we summarise the latest insights into the impact of KIF5A hyperactivity, such as loss of autoinhibition, aggregation, altered cargo binding and microtubule damage. We conclude by discussing possible strategies to counteract these disruptions, with an emphasis on the necessity of restoring axonal transport to physiological levels, a key requirement to maintain neuronal homeostasis.