The Microtubule Associated Protein Tau Regulates KIF1A Pausing Behavior and Motility

Abstract

ABSTRACTMany neurodegenerative diseases result from dysfunction of axonal transport, a highly regulated cellular process responsible for site-specific neuronal cargo delivery. The kinesin-3 family member KIF1A is a key mediator of this process by facilitating long-distance cargo delivery in a spatiotemporally regulated manner. While misregulation of KIF1A cargo delivery is observed in many neurodegenerative diseases, the regulatory mechanisms responsible for KIF1A cargo transport are largely unexplored. Our lab has recently characterized a mechanism for a unique pausing behavior of KIF1A in between processive segments on the microtubule. This behavior, mediated through an interaction between the KIF1A K-loop and the polyglutamylated C-terminal tails of tubulin, helps us further understand how KIF1A conducts long-range cargo transport. However, how this pausing behavior is influenced by other regulatory factors on the microtubule is an unexplored concept. The microtubule associated protein Tau is one potential regulator, as altered Tau function is a pathological marker in many neurodegenerative diseases. However, while the effect of Tau on kinesin-1 and -2 has been extensively characterized, its role in regulating KIF1A transport is greatly unexplored at the behavioral level. Using single-molecule imaging, we have identified Tau-mediated regulation of KIF1A pausing behavior and motility. Specifically, our findings imply a competitive interaction between Tau and KIF1A for the C-terminal tails of tubulin. We introduce a new mechanism of Tau-mediated kinesin regulation by inhibiting the ability of KIF1A to use C-terminal tail reliant pauses to connect multiple processive segments into a longer run length. Moreover, we have correlated this regulatory mechanism to the behavioral dynamics of Tau, further elucidating the function of Tau diffusive and static behavioral state on the microtubule surface. In summary, we introduce a new mechanism of Tau-mediated motility regulation, providing insight on how disruptions in axonal transport can lead to disease state pathology.SIGNIFICANCEKIF1A mediated cargo transport is essential in many cellular processes such as axonal transport and neuronal development. Defects in KIF1A transport have been implicated in neurodegenerative diseases including Alzheimer’s disease and frontotemporal dementia. However, the mechanism of KIF1A’s pathological misregulation remains elusive, highlighting the importance of identifying regulators of KIF1A function. The microtubule associated protein Tau is an attractive potential regulator of KIF1A motility as Tau dysfunction is a hallmark of these neurodegenerative diseases. Here, we demonstrate a direct connection between Tau and KIF1A motility, revealing a unique form of Tau-mediated regulation of axonal transport. Our results provide a molecular foundation for understanding the role of motor protein misregulation in neurodegenerative disease progression.