DYRK1A Regulates the Bidirectional Axonal Transport of APP in Human-Derived Neurons
Iván Fernández Bessone, Jordi Navarro, Emanuel Ricardo Monteiro Martinez, Karina Karmirian, Mariana Holubiec, Matías Alloatti, Livia Goto‐Silva, Cayetana Arnaiz, Daniel Martins‐de‐Souza, Juliana Nascimento, Luciana Bruno, Trinidad Saez, Stevens K. Rehen, Tomás L. Falzone
Abstract
<i>Dyrk1a</i> triplication in Down9s syndrome and its overexpression in Alzheimer9s disease suggest a role for increased DYRK1A activity in the abnormal metabolism of APP. Transport defects are early phenotypes in the progression of Alzheimer9s disease, which lead to APP processing impairments. However, whether DYRK1A regulates the intracellular transport and delivery of APP in human neurons remains unknown. From a proteomic dataset of human cerebral organoids treated with harmine, a DYRK1A inhibitor, we found expression changes in protein clusters associated with the control of microtubule-based transport and in close interaction with the APP vesicle. Live imaging of APP axonal transport in human-derived neurons treated with harmine or overexpressing a dominant negative DYRK1A revealed a reduction in APP vesicle density and enhanced the stochastic behavior of retrograde vesicle transport. Moreover, harmine increased the fraction of slow segmental velocities and changed speed transitions supporting a DYRK1A-mediated effect in the exchange of active motor configuration. Contrarily, the overexpression of DYRK1A in human polarized neurons increased the axonal density of APP vesicles and enhanced the processivity of retrograde APP. In addition, increased DYRK1A activity induced faster retrograde segmental velocities together with significant changes in slow to fast anterograde and retrograde speed transitions, suggesting the facilitation of the active motor configuration. Our results highlight DYRK1A as a modulator of the axonal transport machinery driving APP intracellular distribution in neurons, and stress DYRK1A inhibition as a putative therapeutic intervention to restore APP axonal transport in Down9s syndrome and Alzheimer9s disease. <b>SIGNIFICANCE STATEMENT</b> Axonal transport defects are early events in the progression of neurodegenerative diseases, such as Alzheimer9s disease. However, the molecular mechanisms underlying transport defects remain elusive. <i>Dyrk1a</i> kinase is triplicated in Down9s syndrome and overexpressed in Alzheimer9s disease, suggesting that DYRK1A dysfunction affects molecular pathways leading to early-onset neurodegeneration. Here, we show by live imaging of human-derived neurons that DYRK1A activity differentially regulates the intracellular trafficking of APP. Further, single-particle analysis revealed DYRK1A as a modulator of axonal transport and the configuration of active motors within the APP vesicle. Our work highlights DYRK1A as a regulator of APP axonal transport and metabolism, supporting DYRK1A inhibition as a therapeutic strategy to restore intracellular dynamics in Alzheimer9s disease.