DYRK1A regulates the bidirectional axonal transport of APP in human-derived neurons

IVAN FERNANDEZ BESSONE; JORDI NAVARRO; EMANUEL MARTINEZ; KARINA KARMIRIAN; MARIANA HOLUBIEC; MATIAS ALLOATTI; LIVIA GOTO-SILVA; CAYETANA ARNAIZ YEPEZ; DANIEL MARTINS; JULIANA NASCIMENTO; LUCIANA BRUNO; TRINIDAD SAEZ; STEVENS REHEN; TOMAS FALZONE

JOURNAL OF NEUROSCIENCE

SOC NEUROSCIENCE

Lugar: Washington; Año: 2022

0270-6474

DYRK1A triplication in Down Syndrome and its overexpression in Alzheimer Disease (AD) support a synergistic neurodegenerative effect in the abnormal metabolism of APP. Transport defects are early phenotypes in the progression of AD, which leads to APP processing impairments. However, whether DYRK1A regulates the intracellular transport and delivery of APP in mature neurons remains unknown. Proteomic analysis in harmine-treated human cerebral organoids suggest that microtubule-based transport is regulated by DYRK1A. Live-imaging in harmine-treated human-derived neurons showed reduced distal loading of APP vesicles and increased its stochastic retrograde axonal transport. Contrarily, DYRK1A overexpression increased the retrograde loading and processivity of APP vesicles. DYRK1A inhibition or overexpression showed no changes in vesicle speed transitions, however, modified the fraction and speed of retrograde segmental velocities suggesting a selective modulation of dynein motor activity. We propose DYRK1A as a relevant modulator of APP metabolism through the control of its transport towards the soma and stress DYRK1A inhibition as a therapeutic intervention to restore axonal transport in AD.