The cutting edge of DYRK1A in axonal transport regulation and its implications in neurodegenerative diseases

IVAN FERNANDEZ BESSONE ; MARIANA HOLUBIEC; JORDI NAVARRO CNOBEL; TRINIDAD SAEZ; JOSÉ EMANUEL MARTÍNEZ; TOMAS FALZONE

Congreso; XXXV Annual Meeting of the Argentinian Society for Neuroscience Research; 2020

The complexity of axonal transport regulation has become extremely relevant since it isproposed that transport defects are a necessary step in the progression ofneurodegenerative diseases. Recently, DYRK1A, a dual specificity kinase located inchromosome 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 itsimpact in the molecular pathways that control transport, and identify its role in diseaseprogression, we have inhibited DYRK1A function in human neurons derived from iPSCfor 48 hours using harmine 7,5 uM. We performed live-cell imaging to generate highresolution tracking of the APP vesicle within extended and polarized axons. Thisexperiments revealed a significant reduction on the retrograde component of APPtransport. To probe the role of DYRK1A, we then induced short term DYRK1Aoverexpression that resulted in an opposite phenotype. Moreover, we tested whetherlong term DYRK1A overexpression is linked to different underlying molecularmechanisms. Together, our results highlight the role of DYRK1A in axonal transport bydifferent mechanisms that can be proposed as modulatory of the APP vesicle transport.Our work stress new functions for DYRK1A in the molecular pathways that controlaxonal transport, and shed light on putative therapeutic strategies targeting transportdynamics in neurodegenerative diseases.