Nigral dopaminergic PAK4 prevents neurodegeneration in rat models of Parkinson's disease

So-Yoon Won, Mee-Hee Park, Soon-Tae You, Seung-Won Choi, Hyong-Kyu Kim, Catriona McLean, Suk-Chul Bae, Sang Ryong Kim, Byung Kwan Jin, Kun Ho Lee, Eun-Young Shin, Eung-Gook Kim

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Abstract

Parkinson's disease (PD) is characterized by progressive loss of dopaminergic (DA) neurons in the substantia nigra. No neuroprotective treatments have successfully prevented the progression of this disease. We report that p21-activated kinase 4 (PAK4) is a key survival factor for DA neurons. We observed PAK4 immunoreactivity in rat and human DA neurons in brain tissue, but not in microglia or astrocytes. PAK4 activity was markedly decreased in postmortem brain tissue from PD patients and in rodent models of PD. Expression of constitutively active PAK4S445N/S474E (caPAK4) protected DA neurons in both the 6-hydroxydopamine and a-synuclein rat models of PD and preserved motor function. This neuroprotective effect of caPAK4 was mediated by phosphorylation of CRTC1 [CREB (adenosine 3',5'-monophosphate response element-binding protein)-regulated transcription coactivator] at S215. The nonphosphorylated form of CRTC1S215A compromised the ability of caPAK4 to induce the expression of the CREB target proteins Bcl-2, BDNF, and PGC-1a. Our results support a neuroprotective role for the PAK4-CRTC1S215-CREB signaling pathway and suggest that this pathway may be a useful therapeutic target in PD.

Original languageEnglish
Article number367ra170
Number of pages12
JournalScience Translational Medicine
Volume8
Issue number367
DOIs
Publication statusPublished - 30 Nov 2016
Externally publishedYes

Cite this

Won, So-Yoon ; Park, Mee-Hee ; You, Soon-Tae ; Choi, Seung-Won ; Kim, Hyong-Kyu ; McLean, Catriona ; Bae, Suk-Chul ; Kim, Sang Ryong ; Jin, Byung Kwan ; Lee, Kun Ho ; Shin, Eun-Young ; Kim, Eung-Gook. / Nigral dopaminergic PAK4 prevents neurodegeneration in rat models of Parkinson's disease. In: Science Translational Medicine. 2016 ; Vol. 8, No. 367.
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title = "Nigral dopaminergic PAK4 prevents neurodegeneration in rat models of Parkinson's disease",
abstract = "Parkinson's disease (PD) is characterized by progressive loss of dopaminergic (DA) neurons in the substantia nigra. No neuroprotective treatments have successfully prevented the progression of this disease. We report that p21-activated kinase 4 (PAK4) is a key survival factor for DA neurons. We observed PAK4 immunoreactivity in rat and human DA neurons in brain tissue, but not in microglia or astrocytes. PAK4 activity was markedly decreased in postmortem brain tissue from PD patients and in rodent models of PD. Expression of constitutively active PAK4S445N/S474E (caPAK4) protected DA neurons in both the 6-hydroxydopamine and a-synuclein rat models of PD and preserved motor function. This neuroprotective effect of caPAK4 was mediated by phosphorylation of CRTC1 [CREB (adenosine 3',5'-monophosphate response element-binding protein)-regulated transcription coactivator] at S215. The nonphosphorylated form of CRTC1S215A compromised the ability of caPAK4 to induce the expression of the CREB target proteins Bcl-2, BDNF, and PGC-1a. Our results support a neuroprotective role for the PAK4-CRTC1S215-CREB signaling pathway and suggest that this pathway may be a useful therapeutic target in PD.",
author = "So-Yoon Won and Mee-Hee Park and Soon-Tae You and Seung-Won Choi and Hyong-Kyu Kim and Catriona McLean and Suk-Chul Bae and Kim, {Sang Ryong} and Jin, {Byung Kwan} and Lee, {Kun Ho} and Eun-Young Shin and Eung-Gook Kim",
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Won, S-Y, Park, M-H, You, S-T, Choi, S-W, Kim, H-K, McLean, C, Bae, S-C, Kim, SR, Jin, BK, Lee, KH, Shin, E-Y & Kim, E-G 2016, 'Nigral dopaminergic PAK4 prevents neurodegeneration in rat models of Parkinson's disease', Science Translational Medicine, vol. 8, no. 367, 367ra170. https://doi.org/10.1126/scitranslmed.aaf1629

Nigral dopaminergic PAK4 prevents neurodegeneration in rat models of Parkinson's disease. / Won, So-Yoon; Park, Mee-Hee; You, Soon-Tae; Choi, Seung-Won; Kim, Hyong-Kyu; McLean, Catriona; Bae, Suk-Chul; Kim, Sang Ryong; Jin, Byung Kwan; Lee, Kun Ho; Shin, Eun-Young; Kim, Eung-Gook.

In: Science Translational Medicine, Vol. 8, No. 367, 367ra170, 30.11.2016.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

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AU - Won, So-Yoon

AU - Park, Mee-Hee

AU - You, Soon-Tae

AU - Choi, Seung-Won

AU - Kim, Hyong-Kyu

AU - McLean, Catriona

AU - Bae, Suk-Chul

AU - Kim, Sang Ryong

AU - Jin, Byung Kwan

AU - Lee, Kun Ho

AU - Shin, Eun-Young

AU - Kim, Eung-Gook

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N2 - Parkinson's disease (PD) is characterized by progressive loss of dopaminergic (DA) neurons in the substantia nigra. No neuroprotective treatments have successfully prevented the progression of this disease. We report that p21-activated kinase 4 (PAK4) is a key survival factor for DA neurons. We observed PAK4 immunoreactivity in rat and human DA neurons in brain tissue, but not in microglia or astrocytes. PAK4 activity was markedly decreased in postmortem brain tissue from PD patients and in rodent models of PD. Expression of constitutively active PAK4S445N/S474E (caPAK4) protected DA neurons in both the 6-hydroxydopamine and a-synuclein rat models of PD and preserved motor function. This neuroprotective effect of caPAK4 was mediated by phosphorylation of CRTC1 [CREB (adenosine 3',5'-monophosphate response element-binding protein)-regulated transcription coactivator] at S215. The nonphosphorylated form of CRTC1S215A compromised the ability of caPAK4 to induce the expression of the CREB target proteins Bcl-2, BDNF, and PGC-1a. Our results support a neuroprotective role for the PAK4-CRTC1S215-CREB signaling pathway and suggest that this pathway may be a useful therapeutic target in PD.

AB - Parkinson's disease (PD) is characterized by progressive loss of dopaminergic (DA) neurons in the substantia nigra. No neuroprotective treatments have successfully prevented the progression of this disease. We report that p21-activated kinase 4 (PAK4) is a key survival factor for DA neurons. We observed PAK4 immunoreactivity in rat and human DA neurons in brain tissue, but not in microglia or astrocytes. PAK4 activity was markedly decreased in postmortem brain tissue from PD patients and in rodent models of PD. Expression of constitutively active PAK4S445N/S474E (caPAK4) protected DA neurons in both the 6-hydroxydopamine and a-synuclein rat models of PD and preserved motor function. This neuroprotective effect of caPAK4 was mediated by phosphorylation of CRTC1 [CREB (adenosine 3',5'-monophosphate response element-binding protein)-regulated transcription coactivator] at S215. The nonphosphorylated form of CRTC1S215A compromised the ability of caPAK4 to induce the expression of the CREB target proteins Bcl-2, BDNF, and PGC-1a. Our results support a neuroprotective role for the PAK4-CRTC1S215-CREB signaling pathway and suggest that this pathway may be a useful therapeutic target in PD.

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U2 - 10.1126/scitranslmed.aaf1629

DO - 10.1126/scitranslmed.aaf1629

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