Axonal KPNA1 Signaling Is Involved in the Development of Psychiatric Disorders

Abstract

Karyopherin α1 (KPNA1) forms a complex with nuclear localization sequence containing cargo and importin β1 (IPOB1), facilitating cargo transport into the nucleus. Its elevated expression in neurons and the correlation between mutations and psychiatric disorders imply that KPNA1 has broader significance beyond nucleocytoplasmic transport. Understanding the interplay between psychiatric disorders and signaling at synapses and axon terminals is critical. However, the role of KPNA1 in axonal transport mechanisms remains unclear. Here, we investigated the dynamics of KPNA1 and related factors within axons. Axonal KPNA1, but not IPOB, bound to microtubules. Nevertheless, they exhibited bidirectional motility, and KPNA1 comigrated with molecular motors and vesicle-associated factors. Different mechanisms likely govern axonal transport and nucleocytoplasmic shuttling involving KPNA1 and IPOB1. Mutated KPNA1 associated with psychiatric disorders (KPNA1E448X) predominantly localized to the nucleus and was lost from the axon. Incorporating a nuclear export signal (KPNA1E448X-NES) enhanced its subcellular localization and dynamics in the axon. Axonal KPNA1 signaling plays a crucial role in psychiatric disorders.

Note:
Funding Information: This study received support by JSPS KAKENHI # 22K06220 (K.M.), as well as research grants from Takeda Science Foundation (K.M.), Uehara Memorial Foundation Research Grant (K.M., M.Y.), Hoansha Foundation Research Grant (M.Y.), Naito Foundation Research Grant (M.Y.), Takeda Foundation Visionary Research Grant (Step) (M.Y.), Terumo Life Science Foundation Research Grant (M.Y.), and Organization for Life Science Advancement Programs, University of Fukui (K.M., M.Y.).

Declaration of Interests: The authors declare that they have no conflicts of interest with the contents of this article.

Ethics Approval Statement: All mouse and rat experimental procedures were approved by the Regulations for Animal Research [R04022] and the Safety Management Committee for Genetic Recombination Experiments [R03020] at the University of Fukui. All methods were performed in accordance with the ARRIVE guidelines.

Keywords: Karyopherin α1 (KPNA1), Cytoplasmic dynein, axonal migration, microtubule, Psychiatric disorder