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TFEB/Mitf links impaired nuclear import to autophagolysosomal dysfunction in C9-ALS

Disrupted nucleocytoplasmic transport (NCT) has been implicated in neurodegenerative disease pathogenesis; however, the mechanisms by which disrupted NCT causes neurodegeneration remain unclear. In a Drosophila screen, we identified ref(2)P/p62, a key regulator of autophagy, as a potent suppressor o...

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Autores principales: Cunningham, Kathleen M, Maulding, Kirstin, Ruan, Kai, Senturk, Mumine, Grima, Jonathan C, Sung, Hyun, Zuo, Zhongyuan, Song, Helen, Gao, Junli, Dubey, Sandeep, Rothstein, Jeffrey D, Zhang, Ke, Bellen, Hugo J, Lloyd, Thomas E
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7758070/
https://www.ncbi.nlm.nih.gov/pubmed/33300868
http://dx.doi.org/10.7554/eLife.59419
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author Cunningham, Kathleen M
Maulding, Kirstin
Ruan, Kai
Senturk, Mumine
Grima, Jonathan C
Sung, Hyun
Zuo, Zhongyuan
Song, Helen
Gao, Junli
Dubey, Sandeep
Rothstein, Jeffrey D
Zhang, Ke
Bellen, Hugo J
Lloyd, Thomas E
author_facet Cunningham, Kathleen M
Maulding, Kirstin
Ruan, Kai
Senturk, Mumine
Grima, Jonathan C
Sung, Hyun
Zuo, Zhongyuan
Song, Helen
Gao, Junli
Dubey, Sandeep
Rothstein, Jeffrey D
Zhang, Ke
Bellen, Hugo J
Lloyd, Thomas E
author_sort Cunningham, Kathleen M
collection PubMed
description Disrupted nucleocytoplasmic transport (NCT) has been implicated in neurodegenerative disease pathogenesis; however, the mechanisms by which disrupted NCT causes neurodegeneration remain unclear. In a Drosophila screen, we identified ref(2)P/p62, a key regulator of autophagy, as a potent suppressor of neurodegeneration caused by the GGGGCC hexanucleotide repeat expansion (G4C2 HRE) in C9orf72 that causes amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). We found that p62 is increased and forms ubiquitinated aggregates due to decreased autophagic cargo degradation. Immunofluorescence and electron microscopy of Drosophila tissues demonstrate an accumulation of lysosome-like organelles that precedes neurodegeneration. These phenotypes are partially caused by cytoplasmic mislocalization of Mitf/TFEB, a key transcriptional regulator of autophagolysosomal function. Additionally, TFEB is mislocalized and downregulated in human cells expressing GGGGCC repeats and in C9-ALS patient motor cortex. Our data suggest that the C9orf72-HRE impairs Mitf/TFEB nuclear import, thereby disrupting autophagy and exacerbating proteostasis defects in C9-ALS/FTD.
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spelling pubmed-77580702020-12-28 TFEB/Mitf links impaired nuclear import to autophagolysosomal dysfunction in C9-ALS Cunningham, Kathleen M Maulding, Kirstin Ruan, Kai Senturk, Mumine Grima, Jonathan C Sung, Hyun Zuo, Zhongyuan Song, Helen Gao, Junli Dubey, Sandeep Rothstein, Jeffrey D Zhang, Ke Bellen, Hugo J Lloyd, Thomas E eLife Cell Biology Disrupted nucleocytoplasmic transport (NCT) has been implicated in neurodegenerative disease pathogenesis; however, the mechanisms by which disrupted NCT causes neurodegeneration remain unclear. In a Drosophila screen, we identified ref(2)P/p62, a key regulator of autophagy, as a potent suppressor of neurodegeneration caused by the GGGGCC hexanucleotide repeat expansion (G4C2 HRE) in C9orf72 that causes amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). We found that p62 is increased and forms ubiquitinated aggregates due to decreased autophagic cargo degradation. Immunofluorescence and electron microscopy of Drosophila tissues demonstrate an accumulation of lysosome-like organelles that precedes neurodegeneration. These phenotypes are partially caused by cytoplasmic mislocalization of Mitf/TFEB, a key transcriptional regulator of autophagolysosomal function. Additionally, TFEB is mislocalized and downregulated in human cells expressing GGGGCC repeats and in C9-ALS patient motor cortex. Our data suggest that the C9orf72-HRE impairs Mitf/TFEB nuclear import, thereby disrupting autophagy and exacerbating proteostasis defects in C9-ALS/FTD. eLife Sciences Publications, Ltd 2020-12-10 /pmc/articles/PMC7758070/ /pubmed/33300868 http://dx.doi.org/10.7554/eLife.59419 Text en © 2020, Cunningham et al http://creativecommons.org/licenses/by/4.0/ http://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Cell Biology
Cunningham, Kathleen M
Maulding, Kirstin
Ruan, Kai
Senturk, Mumine
Grima, Jonathan C
Sung, Hyun
Zuo, Zhongyuan
Song, Helen
Gao, Junli
Dubey, Sandeep
Rothstein, Jeffrey D
Zhang, Ke
Bellen, Hugo J
Lloyd, Thomas E
TFEB/Mitf links impaired nuclear import to autophagolysosomal dysfunction in C9-ALS
title TFEB/Mitf links impaired nuclear import to autophagolysosomal dysfunction in C9-ALS
title_full TFEB/Mitf links impaired nuclear import to autophagolysosomal dysfunction in C9-ALS
title_fullStr TFEB/Mitf links impaired nuclear import to autophagolysosomal dysfunction in C9-ALS
title_full_unstemmed TFEB/Mitf links impaired nuclear import to autophagolysosomal dysfunction in C9-ALS
title_short TFEB/Mitf links impaired nuclear import to autophagolysosomal dysfunction in C9-ALS
title_sort tfeb/mitf links impaired nuclear import to autophagolysosomal dysfunction in c9-als
topic Cell Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7758070/
https://www.ncbi.nlm.nih.gov/pubmed/33300868
http://dx.doi.org/10.7554/eLife.59419
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