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Aberrant role of ALK in tau proteinopathy through autophagosomal dysregulation

Proteinopathy in neurodegenerative diseases is typically characterized by deteriorating activity of specific protein aggregates. In tauopathies, including Alzheimer’s disease (AD), tau protein abnormally accumulates and induces dysfunction of the affected neurons. Despite active identification of ta...

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Autores principales: Park, Jisu, Choi, Hyunwoo, Kim, Young Doo, Kim, Seo-Hyun, Kim, Youbin, Gwon, Youngdae, Lee, Dong Young, Park, Sung-Hye, Heo, Won Do, Jung, Yong-Keun
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8758490/
https://www.ncbi.nlm.nih.gov/pubmed/33452442
http://dx.doi.org/10.1038/s41380-020-01003-y
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author Park, Jisu
Choi, Hyunwoo
Kim, Young Doo
Kim, Seo-Hyun
Kim, Youbin
Gwon, Youngdae
Lee, Dong Young
Park, Sung-Hye
Heo, Won Do
Jung, Yong-Keun
author_facet Park, Jisu
Choi, Hyunwoo
Kim, Young Doo
Kim, Seo-Hyun
Kim, Youbin
Gwon, Youngdae
Lee, Dong Young
Park, Sung-Hye
Heo, Won Do
Jung, Yong-Keun
author_sort Park, Jisu
collection PubMed
description Proteinopathy in neurodegenerative diseases is typically characterized by deteriorating activity of specific protein aggregates. In tauopathies, including Alzheimer’s disease (AD), tau protein abnormally accumulates and induces dysfunction of the affected neurons. Despite active identification of tau modifications responsible for tau aggregation, a critical modulator inducing tau proteinopathy by affecting its protein degradation flux is not known. Here, we report that anaplastic lymphoma kinase (ALK), a receptor tyrosine kinase, is crucial for the tau-mediated AD pathology. ALK caused abnormal accumulation of highly phosphorylated tau in the somatodendritic region of neurons through its tyrosine kinase activity. ALK-induced LC3-positive axon swelling and loss of spine density, leading to tau-dependent neuronal degeneration. Notably, ALK activation in neurons impaired Stx17-dependent autophagosome maturation and this defect was reversed by a dominant-negative Grb2. In a Drosophila melanogaster model, transgenic flies neuronally expressing active Drosophila Alk exhibited the aggravated tau rough eye phenotype with retinal degeneration and shortened lifespan. In contrast, expression of kinase-dead Alk blocked these phenotypes. Consistent with the previous RNAseq analysis showing upregulation of ALK expression in AD [1], ALK levels were significantly elevated in the brains of AD patients showing autophagosomal defects. Injection of an ALK.Fc-lentivirus exacerbated memory impairment in 3xTg-AD mice. Conversely, pharmacologic inhibition of ALK activity with inhibitors reversed the memory impairment and tau accumulation in both 3xTg-AD and tauC3 (caspase-cleaved tau) transgenic mice. Together, we propose that aberrantly activated ALK is a bona fide mediator of tau proteinopathy that disrupts autophagosome maturation and causes tau accumulation and aggregation, leading to neuronal dysfunction in AD.
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spelling pubmed-87584902022-01-26 Aberrant role of ALK in tau proteinopathy through autophagosomal dysregulation Park, Jisu Choi, Hyunwoo Kim, Young Doo Kim, Seo-Hyun Kim, Youbin Gwon, Youngdae Lee, Dong Young Park, Sung-Hye Heo, Won Do Jung, Yong-Keun Mol Psychiatry Article Proteinopathy in neurodegenerative diseases is typically characterized by deteriorating activity of specific protein aggregates. In tauopathies, including Alzheimer’s disease (AD), tau protein abnormally accumulates and induces dysfunction of the affected neurons. Despite active identification of tau modifications responsible for tau aggregation, a critical modulator inducing tau proteinopathy by affecting its protein degradation flux is not known. Here, we report that anaplastic lymphoma kinase (ALK), a receptor tyrosine kinase, is crucial for the tau-mediated AD pathology. ALK caused abnormal accumulation of highly phosphorylated tau in the somatodendritic region of neurons through its tyrosine kinase activity. ALK-induced LC3-positive axon swelling and loss of spine density, leading to tau-dependent neuronal degeneration. Notably, ALK activation in neurons impaired Stx17-dependent autophagosome maturation and this defect was reversed by a dominant-negative Grb2. In a Drosophila melanogaster model, transgenic flies neuronally expressing active Drosophila Alk exhibited the aggravated tau rough eye phenotype with retinal degeneration and shortened lifespan. In contrast, expression of kinase-dead Alk blocked these phenotypes. Consistent with the previous RNAseq analysis showing upregulation of ALK expression in AD [1], ALK levels were significantly elevated in the brains of AD patients showing autophagosomal defects. Injection of an ALK.Fc-lentivirus exacerbated memory impairment in 3xTg-AD mice. Conversely, pharmacologic inhibition of ALK activity with inhibitors reversed the memory impairment and tau accumulation in both 3xTg-AD and tauC3 (caspase-cleaved tau) transgenic mice. Together, we propose that aberrantly activated ALK is a bona fide mediator of tau proteinopathy that disrupts autophagosome maturation and causes tau accumulation and aggregation, leading to neuronal dysfunction in AD. Nature Publishing Group UK 2021-01-15 2021 /pmc/articles/PMC8758490/ /pubmed/33452442 http://dx.doi.org/10.1038/s41380-020-01003-y Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Park, Jisu
Choi, Hyunwoo
Kim, Young Doo
Kim, Seo-Hyun
Kim, Youbin
Gwon, Youngdae
Lee, Dong Young
Park, Sung-Hye
Heo, Won Do
Jung, Yong-Keun
Aberrant role of ALK in tau proteinopathy through autophagosomal dysregulation
title Aberrant role of ALK in tau proteinopathy through autophagosomal dysregulation
title_full Aberrant role of ALK in tau proteinopathy through autophagosomal dysregulation
title_fullStr Aberrant role of ALK in tau proteinopathy through autophagosomal dysregulation
title_full_unstemmed Aberrant role of ALK in tau proteinopathy through autophagosomal dysregulation
title_short Aberrant role of ALK in tau proteinopathy through autophagosomal dysregulation
title_sort aberrant role of alk in tau proteinopathy through autophagosomal dysregulation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8758490/
https://www.ncbi.nlm.nih.gov/pubmed/33452442
http://dx.doi.org/10.1038/s41380-020-01003-y
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