Poul Henning Jensen

Activity of translation regulator eukaryotic elongation factor-2 kinase is increased in Parkinson disease brain and its inhibition reduces alpha synuclein toxicity

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

Standard

Activity of translation regulator eukaryotic elongation factor-2 kinase is increased in Parkinson disease brain and its inhibition reduces alpha synuclein toxicity. / Jan, Asad; Jansonius, Brandon; Delaidelli, Alberto; Bhanshali, Forum; An, Yi Andy; Ferreira, Nelson; Smits, Lisa M; Negri, Gian Luca; Schwamborn, Jens C; Jensen, Poul H; Mackenzie, Ian R; Taubert, Stefan; Sorensen, Poul H.

In: Acta Neuropathologica Communications, Vol. 6, No. 1, 54, 2018.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

Harvard

Jan, A, Jansonius, B, Delaidelli, A, Bhanshali, F, An, YA, Ferreira, N, Smits, LM, Negri, GL, Schwamborn, JC, Jensen, PH, Mackenzie, IR, Taubert, S & Sorensen, PH 2018, 'Activity of translation regulator eukaryotic elongation factor-2 kinase is increased in Parkinson disease brain and its inhibition reduces alpha synuclein toxicity', Acta Neuropathologica Communications, vol. 6, no. 1, 54. https://doi.org/10.1186/s40478-018-0554-9

APA

Jan, A., Jansonius, B., Delaidelli, A., Bhanshali, F., An, Y. A., Ferreira, N., Smits, L. M., Negri, G. L., Schwamborn, J. C., Jensen, P. H., Mackenzie, I. R., Taubert, S., & Sorensen, P. H. (2018). Activity of translation regulator eukaryotic elongation factor-2 kinase is increased in Parkinson disease brain and its inhibition reduces alpha synuclein toxicity. Acta Neuropathologica Communications, 6(1), [54]. https://doi.org/10.1186/s40478-018-0554-9

CBE

Jan A, Jansonius B, Delaidelli A, Bhanshali F, An YA, Ferreira N, Smits LM, Negri GL, Schwamborn JC, Jensen PH, Mackenzie IR, Taubert S, Sorensen PH. 2018. Activity of translation regulator eukaryotic elongation factor-2 kinase is increased in Parkinson disease brain and its inhibition reduces alpha synuclein toxicity. Acta Neuropathologica Communications. 6(1):Article 54. https://doi.org/10.1186/s40478-018-0554-9

MLA

Vancouver

Author

Jan, Asad ; Jansonius, Brandon ; Delaidelli, Alberto ; Bhanshali, Forum ; An, Yi Andy ; Ferreira, Nelson ; Smits, Lisa M ; Negri, Gian Luca ; Schwamborn, Jens C ; Jensen, Poul H ; Mackenzie, Ian R ; Taubert, Stefan ; Sorensen, Poul H. / Activity of translation regulator eukaryotic elongation factor-2 kinase is increased in Parkinson disease brain and its inhibition reduces alpha synuclein toxicity. In: Acta Neuropathologica Communications. 2018 ; Vol. 6, No. 1.

Bibtex

@article{dd6c4fca394b4b31aff75577befaba00,
title = "Activity of translation regulator eukaryotic elongation factor-2 kinase is increased in Parkinson disease brain and its inhibition reduces alpha synuclein toxicity",
abstract = "Parkinson disease (PD) is the second most common neurodegenerative disorder and the leading neurodegenerative cause of motor disability. Pathologic accumulation of aggregated alpha synuclein (AS) protein in brain, and imbalance in the nigrostriatal system due to the loss of dopaminergic neurons in the substantia nigra- pars compacta, are hallmark features in PD. AS aggregation and propagation are considered to trigger neurotoxic mechanisms in PD, including mitochondrial deficits and oxidative stress. The eukaryotic elongation factor-2 kinase (eEF2K) mediates critical regulation of dendritic mRNA translation and is a crucial molecule in diverse forms of synaptic plasticity. Here we show that eEF2K activity, assessed by immuonohistochemical detection of eEF2 phosphorylation on serine residue 56, is increased in postmortem PD midbrain and hippocampus. Induction of aggressive, AS-related motor phenotypes in a transgenic PD M83 mouse model also increased brain eEF2K expression and activity. In cultures of dopaminergic N2A cells, overexpression of wild-type human AS or the A53T mutant increased eEF2K activity. eEF2K inhibition prevented the cytotoxicity associated with AS overexpression in N2A cells by improving mitochondrial function and reduced oxidative stress. Furthermore, genetic deletion of the eEF2K ortholog efk-1 in C. elegans attenuated human A53T AS induced defects in behavioural assays reliant on dopaminergic neuron function. These data suggest a role for eEF2K activity in AS toxicity, and support eEF2K inhibition as a potential target in reducing AS-induced oxidative stress in PD.",
keywords = "eEF2K, Parkinson disease, mRNA translation, Alpha synuclein",
author = "Asad Jan and Brandon Jansonius and Alberto Delaidelli and Forum Bhanshali and An, {Yi Andy} and Nelson Ferreira and Smits, {Lisa M} and Negri, {Gian Luca} and Schwamborn, {Jens C} and Jensen, {Poul H} and Mackenzie, {Ian R} and Stefan Taubert and Sorensen, {Poul H}",
year = "2018",
doi = "10.1186/s40478-018-0554-9",
language = "English",
volume = "6",
journal = "Acta Neuropathologica Communications",
issn = "2051-5960",
publisher = "BioMed Central Ltd.",
number = "1",

}

RIS

TY - JOUR

T1 - Activity of translation regulator eukaryotic elongation factor-2 kinase is increased in Parkinson disease brain and its inhibition reduces alpha synuclein toxicity

AU - Jan, Asad

AU - Jansonius, Brandon

AU - Delaidelli, Alberto

AU - Bhanshali, Forum

AU - An, Yi Andy

AU - Ferreira, Nelson

AU - Smits, Lisa M

AU - Negri, Gian Luca

AU - Schwamborn, Jens C

AU - Jensen, Poul H

AU - Mackenzie, Ian R

AU - Taubert, Stefan

AU - Sorensen, Poul H

PY - 2018

Y1 - 2018

N2 - Parkinson disease (PD) is the second most common neurodegenerative disorder and the leading neurodegenerative cause of motor disability. Pathologic accumulation of aggregated alpha synuclein (AS) protein in brain, and imbalance in the nigrostriatal system due to the loss of dopaminergic neurons in the substantia nigra- pars compacta, are hallmark features in PD. AS aggregation and propagation are considered to trigger neurotoxic mechanisms in PD, including mitochondrial deficits and oxidative stress. The eukaryotic elongation factor-2 kinase (eEF2K) mediates critical regulation of dendritic mRNA translation and is a crucial molecule in diverse forms of synaptic plasticity. Here we show that eEF2K activity, assessed by immuonohistochemical detection of eEF2 phosphorylation on serine residue 56, is increased in postmortem PD midbrain and hippocampus. Induction of aggressive, AS-related motor phenotypes in a transgenic PD M83 mouse model also increased brain eEF2K expression and activity. In cultures of dopaminergic N2A cells, overexpression of wild-type human AS or the A53T mutant increased eEF2K activity. eEF2K inhibition prevented the cytotoxicity associated with AS overexpression in N2A cells by improving mitochondrial function and reduced oxidative stress. Furthermore, genetic deletion of the eEF2K ortholog efk-1 in C. elegans attenuated human A53T AS induced defects in behavioural assays reliant on dopaminergic neuron function. These data suggest a role for eEF2K activity in AS toxicity, and support eEF2K inhibition as a potential target in reducing AS-induced oxidative stress in PD.

AB - Parkinson disease (PD) is the second most common neurodegenerative disorder and the leading neurodegenerative cause of motor disability. Pathologic accumulation of aggregated alpha synuclein (AS) protein in brain, and imbalance in the nigrostriatal system due to the loss of dopaminergic neurons in the substantia nigra- pars compacta, are hallmark features in PD. AS aggregation and propagation are considered to trigger neurotoxic mechanisms in PD, including mitochondrial deficits and oxidative stress. The eukaryotic elongation factor-2 kinase (eEF2K) mediates critical regulation of dendritic mRNA translation and is a crucial molecule in diverse forms of synaptic plasticity. Here we show that eEF2K activity, assessed by immuonohistochemical detection of eEF2 phosphorylation on serine residue 56, is increased in postmortem PD midbrain and hippocampus. Induction of aggressive, AS-related motor phenotypes in a transgenic PD M83 mouse model also increased brain eEF2K expression and activity. In cultures of dopaminergic N2A cells, overexpression of wild-type human AS or the A53T mutant increased eEF2K activity. eEF2K inhibition prevented the cytotoxicity associated with AS overexpression in N2A cells by improving mitochondrial function and reduced oxidative stress. Furthermore, genetic deletion of the eEF2K ortholog efk-1 in C. elegans attenuated human A53T AS induced defects in behavioural assays reliant on dopaminergic neuron function. These data suggest a role for eEF2K activity in AS toxicity, and support eEF2K inhibition as a potential target in reducing AS-induced oxidative stress in PD.

KW - eEF2K

KW - Parkinson disease

KW - mRNA translation

KW - Alpha synuclein

UR - http://www.scopus.com/inward/record.url?scp=85061320398&partnerID=8YFLogxK

U2 - 10.1186/s40478-018-0554-9

DO - 10.1186/s40478-018-0554-9

M3 - Journal article

C2 - 29961428

VL - 6

JO - Acta Neuropathologica Communications

JF - Acta Neuropathologica Communications

SN - 2051-5960

IS - 1

M1 - 54

ER -