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 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 CRTC1S215Acompromised 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-CRTC1S215-CREB signaling pathway and suggest that this pathway may be a useful therapeutic target in PD.
authors.affiliation: Department of Biochemistry and Signaling Disorder Research Center, College of Medicine, Chungbuk National University, Cheongju 28644, South Korea.
authors.forename: So-Yoon
authors.initials: SY
authors.lastname: Won
authors.affiliation: Department of Biochemistry and Signaling Disorder Research Center, College of Medicine, Chungbuk National University, Cheongju 28644, South Korea.
authors.forename: Mee-Hee
authors.initials: MH
authors.lastname: Park
authors.affiliation: Department of Biochemistry and Signaling Disorder Research Center, College of Medicine, Chungbuk National University, Cheongju 28644, South Korea.
authors.forename: Soon-Tae
authors.initials: ST
authors.lastname: You
authors.affiliation: Department of Biochemistry and Signaling Disorder Research Center, College of Medicine, Chungbuk National University, Cheongju 28644, South Korea.
authors.forename: Seung-Won
authors.initials: SW
authors.lastname: Choi
authors.affiliation: Department of Medicine and Microbiology, College of Medicine, Chungbuk National University, Cheongju 28644, South Korea.
authors.forename: Hyong-Kyu
authors.initials: HK
authors.lastname: Kim
authors.affiliation: Department of Pathology, The Alfred Hospital, Melbourne, Victoria 3004, Australia.
authors.forename: Catriona
authors.initials: C
authors.lastname: McLean
authors.affiliation: Department of Biochemistry, School of Medicine, Institute for Tumor Research, Chungbuk National University, Cheongju 28644, South Korea.
authors.forename: Suk-Chul
authors.initials: SC
authors.lastname: Bae
authors.affiliation: School of Life Sciences, BK21 plus KNU Creative BioResearch Group, Kyungpook National University, Daegu 41566, South Korea.|Brain Science and Engineering Institute, Kyungpook National University, Daegu 41944, South Korea.
authors.forename: Sang Ryong
authors.initials: SR
authors.lastname: Kim
authors.affiliation: Department of Biochemistry & Molecular Biology, Department of Neuroscience, Neurodegeneration Control Research Center, School of Medicine, Kyung Hee University, Seoul 02447, South Korea.
authors.forename: Byung Kwan
authors.initials: BK
authors.lastname: Jin
authors.affiliation: National Research Center for Dementia, Chosun University, Gwangju 61452, South Korea.|Department of Biomedical Science, Chosun University, Gwangju 61452, South Korea.
authors.forename: Kun Ho
authors.initials: KH
authors.lastname: Lee
authors.affiliation: Department of Biochemistry and Signaling Disorder Research Center, College of Medicine, Chungbuk National University, Cheongju 28644, South Korea.
authors.forename: Eun-Young
authors.initials: EY
authors.lastname: Shin
authors.affiliation: Department of Biochemistry and Signaling Disorder Research Center, College of Medicine, Chungbuk National University, Cheongju 28644, South Korea. egkim@chungbuk.ac.kr.
authors.forename: Eung-Gook
authors.initials: EG
authors.lastname: Kim
mesh_terms: D000818:Animals; D001921:Brain / Q000473:pathology; D002470:Cell Survival; D004195:Disease Models, Animal; D018450:Disease Progression; D004298:Dopamine / Q000737:chemistry; D005260:Female; D006801:Humans; D019636:Neurodegenerative Diseases / Q000473:pathology*; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D010300:Parkinson Disease / Q000473:pathology*; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D013378:Substantia Nigra / Q000473:pathology*; D014157:Transcription Factors / Q000378:metabolism; D054462:p21-Activated Kinases / Q000378:metabolism*
chemical_list: C500984:CRTC1 protein, human; D014157:Transcription Factors; C116367:PAK4 protein, human; D054462:p21-Activated Kinases; D004298:Dopamine