The complexity of axonal transport regulation has become extremely relevant since it is proposed that transport defects are a necessary step in the progression of neurodegenerative diseases. Recently, DYRK1A, a dual specificity kinase located in chromosome 21 has been associated with abnormal early aging of the nervous system, since it modulate APP and tau protein.
To unravel whether DYRK1A has a role in axonal transport regulation, understand its impact in the molecular pathways that control transport, and identify its role in disease progression, we have inhibited DYRK1A function in human neurons derived from iPSC for 48 hours using harmine 7,5 uM. We performed live-cell imaging to generate high resolution tracking of the APP vesicle within extended and polarized axons. This experiments revealed a significant reduction on the retrograde component of APP transport. To probe the role of DYRK1A, we then induced short term DYRK1A overexpression that resulted in an opposite phenotype. Moreover, we tested whether long term DYRK1A overexpression is linked to different underlying molecular mechanisms. Together, our results highlight the role of DYRK1A in axonal transport by different mechanisms that can be proposed as modulatory of the APP vesicle transport.
Our work stress new functions for DYRK1A in the molecular pathways that control axonal transport, and shed light on putative therapeutic strategies targeting transport dynamics in neurodegenerative diseases.