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

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

doi:10.1038/s41598-021-90822-2

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

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

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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.

Original language	English
Article number	11474
Pages (from-to)	1-16
Number of pages	16
Journal	Scientific Reports
Volume	11
DOIs	https://doi.org/10.1038/s41598-021-90822-2
Publication status	Published - 1 Jun 2021

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Copyright the Author(s) 2021. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

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Foster, A. D., Flynn, L. L., Cluning, C., Cheng, F., Davidson, J. M., Lee, A., Polain, N., Mejzini, R., Farrawell, N., Yerbury, J. J., Layfield, R., Akkari, P. A., & Rea, S. L. (2021). p62 overexpression induces TDP-43 cytoplasmic mislocalisation, aggregation and cleavage and neuronal death. Scientific Reports, 11, 1-16. Article 11474. https://doi.org/10.1038/s41598-021-90822-2

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title = "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 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.",

author = "Foster, {A. D.} and Flynn, {L. L.} and C. Cluning and F. Cheng and Davidson, {J. M.} and A. Lee and N. Polain and R. Mejzini and N. Farrawell and Yerbury, {J. J.} and R. Layfield and Akkari, {P. A.} and Rea, {S. L.}",

note = "Copyright the Author(s) 2021. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.",

year = "2021",

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doi = "10.1038/s41598-021-90822-2",

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T1 - p62 overexpression induces TDP-43 cytoplasmic mislocalisation, aggregation and cleavage and neuronal death

AU - Foster, A. D.

AU - Flynn, L. L.

AU - Cluning, C.

AU - Cheng, F.

AU - Davidson, J. M.

AU - Lee, A.

AU - Polain, N.

AU - Mejzini, R.

AU - Farrawell, N.

AU - Yerbury, J. J.

AU - Layfield, R.

AU - Akkari, P. A.

AU - Rea, S. L.

N1 - Copyright the Author(s) 2021. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

PY - 2021/6/1

Y1 - 2021/6/1

N2 - 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.

AB - 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.

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VL - 11

SP - 1

EP - 16

JO - Scientific Reports

JF - Scientific Reports

M1 - 11474

ER -

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

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