Direct observation of importin α family member KPNA1 in axonal transport with or without a schizophrenia-related mutation

Karyopherin α1 (KPNA1)/(human importin α5; mouse importin α1) facilitates cargo transport into the nucleus by forming a complex with a nuclear localization sequence containing cargo and importin β1 (IPOB1). The elevated KPNA1 expression in neurons and the correlation between mutations and psychiatric disorders suggest its broader significance beyond nucleocytoplasmic transport. Although KPNA1 is localized in the neurites of neurons, its role in axonal transport mechanisms remains unclear, and data on the connection between psychiatric disorders and signaling at the periphery of neurons remain limited. To address this knowledge gap, we investigated the dynamics of KPNA1 and related factors within axons. Our results showed that many of the axonal KPNA1 did not form a complex with IPOB1 in noninjured steady-state neurons. Axonal KPNA1 exhibited relatively stationary mobility and some showed bidirectional motility with fluctuating motion. KPNA1 partly comigrated with endosome/lysosome-associated factors, suggesting the presence of novel mechanisms underlie axonal transport and nucleocytoplasmic shuttling involving KPNA1 and IPOB1. Mutated KPNA1, which has been shown to be associated with psychiatric disorders (KPNA1^E448X), was predominantly localized to the nucleus and lost from the axon. Incorporating a nuclear export signal (KPNA1^E448X-NES) enhanced its subcellular localization and dynamics in the axon. Our findings demonstrate that KPNA1 functions not only as a shuttle between the cytoplasm and nucleus but also as a transporter in neuronal axons, relying on the endosomes for movement away from the nucleus with relatively slow net motions. Furthermore, a mutation in the Kpna1 gene can affect the dynamics of axonal transport. The insights from these mutations provide valuable knowledge for expanding our understanding of psychiatric disorders and facilitate the development of novel treatment strategies.