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

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...

Full description

Saved in:
Bibliographic Details
Published in:Science translational medicine 2016-11, Vol.8 (367), p.367ra170-367ra170
Main Authors: 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
Format: Article
Language:English
Subjects:
Animals
Brain - pathology
Cell Survival
Disease Models, Animal
Disease Progression
Dopamine - chemistry
Female
Humans
Neurodegenerative Diseases - pathology
Neurons - metabolism
Neurons - pathology
p21-Activated Kinases - metabolism
Parkinson Disease - pathology
Phosphorylation
Rats
Rats, Sprague-Dawley
Signal Transduction
Substantia Nigra - pathology
Transcription Factors - metabolism
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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 PAK4 (caPAK4) protected DA neurons in both the 6-hydroxydopamine and α-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 CRTC1 compromised the ability of caPAK4 to induce the expression of the CREB target proteins Bcl-2, BDNF, and PGC-1α. Our results support a neuroprotective role for the PAK4-CRTC1 -CREB signaling pathway and suggest that this pathway may be a useful therapeutic target in PD.
ISSN:1946-6234
1946-6242
DOI:10.1126/scitranslmed.aaf1629