RT Journal Article
SR Electronic
T1 DYRK1A Regulates the Bidirectional Axonal Transport of APP in Human-Derived Neurons
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 6344
OP 6358
DO 10.1523/JNEUROSCI.2551-21.2022
VO 42
IS 33
A1 Iván Fernandez Bessone
A1 Jordi Navarro
A1 Emanuel Martinez
A1 Karina Karmirian
A1 Mariana Holubiec
A1 Matias Alloatti
A1 Livia Goto-Silva
A1 Cayetana Arnaiz Yepez
A1 Daniel Martins-de-Souza
A1 Juliana Minardi Nascimento
A1 Luciana Bruno
A1 Trinidad M. Saez
A1 Stevens K. Rehen
A1 Tomás L. Falzone
YR 2022
UL http://www.jneurosci.org/content/42/33/6344.abstract
AB Dyrk1a triplication in Down's syndrome and its overexpression in Alzheimer's disease suggest a role for increased DYRK1A activity in the abnormal metabolism of APP. Transport defects are early phenotypes in the progression of Alzheimer's 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 Down's syndrome and Alzheimer's disease.SIGNIFICANCE STATEMENT Axonal transport defects are early events in the progression of neurodegenerative diseases, such as Alzheimer's disease. However, the molecular mechanisms underlying transport defects remain elusive. Dyrk1a kinase is triplicated in Down's syndrome and overexpressed in Alzheimer's 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 Alzheimer's disease.