Artículo
DYRK1A Regulates the Bidirectional Axonal Transport of APP in Human-Derived Neurons
Fernández Bessone, Iván; Navarro, Jordi; Martinez, Emanuel; Karmirian, Karina; Holubiec, Mariana Ines
; Alloatti, Matías
; Goto Silva, Livia; Arnaiz Yépez, Cayetana
; Martins De Souza, Daniel; Nascimento, Juliana Minardi; Bruno, Luciana; Saez, Trinidad María de Los Milagros
; Rehen, Stevens K.; Falzone, Tomas Luis
Fecha de publicación:
08/2022
Editorial:
Society for Neuroscience
Revista:
Journal of Neuroscience
ISSN:
0270-6474
Idioma:
Inglés
Tipo de recurso:
Artículo publicado
Clasificación temática:
Resumen
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.
Palabras clave:
ALZHEIMER’S DISEASE
,
APP
,
AXONAL TRANSPORT
,
DYRK1A
,
HUMAN NEURONS
,
MOTOR PROTEINS
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Identificadores
Colecciones
Articulos(IBIOBA - MPSP)
Articulos de INST. D/INV.EN BIOMED.DE BS AS-CONICET-INST. PARTNER SOCIEDAD MAX PLANCK
Articulos de INST. D/INV.EN BIOMED.DE BS AS-CONICET-INST. PARTNER SOCIEDAD MAX PLANCK
Citación
Fernández Bessone, Iván; Navarro, Jordi; Martinez, Emanuel; Karmirian, Karina; Holubiec, Mariana Ines; et al.; DYRK1A Regulates the Bidirectional Axonal Transport of APP in Human-Derived Neurons; Society for Neuroscience; Journal of Neuroscience; 42; 33; 8-2022; 6344-6358
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