p62 overexpression induces TDP-43 cytoplasmic mislocalisation, aggregation and cleavage and neuronal death

Abstract Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) that exist on a spectrum of neurodegenerative disease. A hallmark of pathology is cytoplasmic TDP-43 aggregates within neurons, observed in 97% of ALS cases and ~ 50% of FTLD cases. This mislocalisation from th...

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Autores principales:	A. D. Foster, L. L. Flynn, C. Cluning, F. Cheng, J. M. Davidson, A. Lee, N. Polain, R. Mejzini, N. Farrawell, J. J. Yerbury, R. Layfield, P. A. Akkari, S. L. Rea
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/df72a4378b5f4a91bdcc3aec3c0d13ff
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spelling	oai:doaj.org-article:df72a4378b5f4a91bdcc3aec3c0d13ff2021-12-02T18:25:03Zp62 overexpression induces TDP-43 cytoplasmic mislocalisation, aggregation and cleavage and neuronal death10.1038/s41598-021-90822-22045-2322https://doaj.org/article/df72a4378b5f4a91bdcc3aec3c0d13ff2021-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-90822-2https://doaj.org/toc/2045-2322Abstract Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) that exist on a spectrum of neurodegenerative disease. A hallmark of pathology is cytoplasmic TDP-43 aggregates within neurons, observed in 97% of ALS cases and ~ 50% of FTLD cases. This mislocalisation from the nucleus into the cytoplasm and TDP-43 cleavage are associated with pathology, however, the drivers of these changes are unknown. p62 is invariably also present within these aggregates. We show that p62 overexpression causes TDP-43 mislocalisation into cytoplasmic aggregates, and aberrant TDP-43 cleavage that was dependent on both the PB1 and ubiquitin-associated (UBA) domains of p62. We further show that p62 overexpression induces neuron death. We found that stressors (proteasome inhibition and arsenic) increased p62 expression and that this shifted the nuclear:cytoplasmic TDP-43 ratio. Overall, our study suggests that environmental factors that increase p62 may thereby contribute to TDP-43 pathology in ALS and FTLD.A. D. FosterL. L. FlynnC. CluningF. ChengJ. M. DavidsonA. LeeN. PolainR. MejziniN. FarrawellJ. J. YerburyR. LayfieldP. A. AkkariS. L. ReaNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-16 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q A. D. Foster L. L. Flynn C. Cluning F. Cheng J. M. Davidson A. Lee N. Polain R. Mejzini N. Farrawell J. J. Yerbury R. Layfield P. A. Akkari S. L. Rea p62 overexpression induces TDP-43 cytoplasmic mislocalisation, aggregation and cleavage and neuronal death
description	Abstract Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) that exist on a spectrum of neurodegenerative disease. A hallmark of pathology is cytoplasmic TDP-43 aggregates within neurons, observed in 97% of ALS cases and ~ 50% of FTLD cases. This mislocalisation from the nucleus into the cytoplasm and TDP-43 cleavage are associated with pathology, however, the drivers of these changes are unknown. p62 is invariably also present within these aggregates. We show that p62 overexpression causes TDP-43 mislocalisation into cytoplasmic aggregates, and aberrant TDP-43 cleavage that was dependent on both the PB1 and ubiquitin-associated (UBA) domains of p62. We further show that p62 overexpression induces neuron death. We found that stressors (proteasome inhibition and arsenic) increased p62 expression and that this shifted the nuclear:cytoplasmic TDP-43 ratio. Overall, our study suggests that environmental factors that increase p62 may thereby contribute to TDP-43 pathology in ALS and FTLD.
format	article
author	A. D. Foster L. L. Flynn C. Cluning F. Cheng J. M. Davidson A. Lee N. Polain R. Mejzini N. Farrawell J. J. Yerbury R. Layfield P. A. Akkari S. L. Rea
author_facet	A. D. Foster L. L. Flynn C. Cluning F. Cheng J. M. Davidson A. Lee N. Polain R. Mejzini N. Farrawell J. J. Yerbury R. Layfield P. A. Akkari S. L. Rea
author_sort	A. D. Foster
title	p62 overexpression induces TDP-43 cytoplasmic mislocalisation, aggregation and cleavage and neuronal death
title_short	p62 overexpression induces TDP-43 cytoplasmic mislocalisation, aggregation and cleavage and neuronal death
title_full	p62 overexpression induces TDP-43 cytoplasmic mislocalisation, aggregation and cleavage and neuronal death
title_fullStr	p62 overexpression induces TDP-43 cytoplasmic mislocalisation, aggregation and cleavage and neuronal death
title_full_unstemmed	p62 overexpression induces TDP-43 cytoplasmic mislocalisation, aggregation and cleavage and neuronal death
title_sort	p62 overexpression induces tdp-43 cytoplasmic mislocalisation, aggregation and cleavage and neuronal death
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/df72a4378b5f4a91bdcc3aec3c0d13ff
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p62 overexpression induces TDP-43 cytoplasmic mislocalisation, aggregation and cleavage and neuronal death

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