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Research Articles, Cellular/Molecular

DYRK1A Regulates the Bidirectional Axonal Transport of APP in Human-Derived Neurons

Iván Fernandez Bessone, Jordi Navarro, Emanuel Martinez, Karina Karmirian, Mariana Holubiec, Matias Alloatti, Livia Goto-Silva, Cayetana Arnaiz Yepez, Daniel Martins-de-Souza, Juliana Minardi Nascimento, Luciana Bruno, Trinidad M. Saez, Stevens K. Rehen and Tomás L. Falzone
Journal of Neuroscience 17 August 2022, 42 (33) 6344-6358; DOI: https://doi.org/10.1523/JNEUROSCI.2551-21.2022
Iván Fernandez Bessone
1Instituto de Biología Celular y Neurociencia IBCN, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina C1121ABG
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Jordi Navarro
1Instituto de Biología Celular y Neurociencia IBCN, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina C1121ABG
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Emanuel Martinez
1Instituto de Biología Celular y Neurociencia IBCN, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina C1121ABG
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Karina Karmirian
2D'Or Institute for Research and Education, Rio de Janeiro, Brasil, RJ, 22281-100
3Departamento de Genética, Instituto de Biologia, Universidade Federal do Rio de Janeiro, Brasil, RJ, 21941-902
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Mariana Holubiec
1Instituto de Biología Celular y Neurociencia IBCN, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina C1121ABG
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Matias Alloatti
1Instituto de Biología Celular y Neurociencia IBCN, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina C1121ABG
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Livia Goto-Silva
2D'Or Institute for Research and Education, Rio de Janeiro, Brasil, RJ, 22281-100
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Cayetana Arnaiz Yepez
1Instituto de Biología Celular y Neurociencia IBCN, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina C1121ABG
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Daniel Martins-de-Souza
2D'Or Institute for Research and Education, Rio de Janeiro, Brasil, RJ, 22281-100
4Laboratory of Neuroproteomics, University of Campinas Campinas, Brasil, SP, 13083-970
5Instituto Nacional de Biomarcadores Em Neuropsiquiatria, Conselho Nacional de Desenvolvimento Científico e Tecnológico, São Paulo, Brasil, SP, 13083-970
6Experimental Medicine Research Cluster, University of Campinas, Campinas, Brasil, SP, 13083-970
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Juliana Minardi Nascimento
4Laboratory of Neuroproteomics, University of Campinas Campinas, Brasil, SP, 13083-970
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Luciana Bruno
7Instituto de Cálculo, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Argentina C1428EGA
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Trinidad M. Saez
1Instituto de Biología Celular y Neurociencia IBCN, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina C1121ABG
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Stevens K. Rehen
2D'Or Institute for Research and Education, Rio de Janeiro, Brasil, RJ, 22281-100
3Departamento de Genética, Instituto de Biologia, Universidade Federal do Rio de Janeiro, Brasil, RJ, 21941-902
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Tomás L. Falzone
1Instituto de Biología Celular y Neurociencia IBCN, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina C1121ABG
8Instituto de Investigación en Biomedicina de Buenos Aires, Partner Institute of the Max Planck Society, Buenos Aires, Argentina C1425FQD
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Abstract

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.

  • Alzheimer's disease
  • APP
  • axonal transport
  • DYRK1A
  • human neurons
  • motor proteins

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The Journal of Neuroscience: 42 (33)
Journal of Neuroscience
Vol. 42, Issue 33
17 Aug 2022
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DYRK1A Regulates the Bidirectional Axonal Transport of APP in Human-Derived Neurons
Iván Fernandez Bessone, Jordi Navarro, Emanuel Martinez, Karina Karmirian, Mariana Holubiec, Matias Alloatti, Livia Goto-Silva, Cayetana Arnaiz Yepez, Daniel Martins-de-Souza, Juliana Minardi Nascimento, Luciana Bruno, Trinidad M. Saez, Stevens K. Rehen, Tomás L. Falzone
Journal of Neuroscience 17 August 2022, 42 (33) 6344-6358; DOI: 10.1523/JNEUROSCI.2551-21.2022

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DYRK1A Regulates the Bidirectional Axonal Transport of APP in Human-Derived Neurons
Iván Fernandez Bessone, Jordi Navarro, Emanuel Martinez, Karina Karmirian, Mariana Holubiec, Matias Alloatti, Livia Goto-Silva, Cayetana Arnaiz Yepez, Daniel Martins-de-Souza, Juliana Minardi Nascimento, Luciana Bruno, Trinidad M. Saez, Stevens K. Rehen, Tomás L. Falzone
Journal of Neuroscience 17 August 2022, 42 (33) 6344-6358; DOI: 10.1523/JNEUROSCI.2551-21.2022
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Keywords

  • Alzheimer's disease
  • APP
  • axonal transport
  • DYRK1A
  • human neurons
  • motor proteins

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