Molecules and Cells

  • 제44권7호
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  • Pages.493-499
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  • 2021
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  • 1016-8478(pISSN)
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  • 0219-1032(eISSN)
한국분자세포생물학회 (Korean Society for Molecular and Cellular Biology)
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cAMP Response Element-Binding Protein- and Phosphorylation-Dependent Regulation of Tyrosine Hydroxylase by PAK4: Implications for Dopamine Replacement Therapy

  • Won, So-Yoon (Department of Biological Sciences, Konkuk University) ;
  • You, Soon-Tae (Department of Neurosurgery, The Catholic University of Korea, St. Vincent's Hospital) ;
  • Choi, Seung-Won (Daegu Gyeongbuk Institute of Science & Technology) ;
  • McLean, Catriona (Department of Pathology, The Alfred Hospital) ;
  • Shin, Eun-Young (Department of Biochemistry, Chungbuk National University College of Medicine) ;
  • Kim, Eung-Gook (Department of Biochemistry, Chungbuk National University College of Medicine)
  • 투고 : 2020.12.20
  • 심사 : 2021.05.13
  • 발행 : 2021.07.31
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초록

Parkinson's disease (PD) is characterized by a progressive loss of dopamine-producing neurons in the midbrain, which results in decreased dopamine levels accompanied by movement symptoms. Oral administration of l-3,4-dihydroxyphenylalanine (L-dopa), the precursor of dopamine, provides initial symptomatic relief, but abnormal involuntary movements develop later. A deeper understanding of the regulatory mechanisms underlying dopamine homeostasis is thus critically needed for the development of a successful treatment. Here, we show that p21-activated kinase 4 (PAK4) controls dopamine levels. Constitutively active PAK4 (caPAK4) stimulated transcription of tyrosine hydroxylase (TH) via the cAMP response element-binding protein (CREB) transcription factor. Moreover, caPAK4 increased the catalytic activity of TH through its phosphorylation of S40, which is essential for TH activation. Consistent with this result, in human midbrain tissues, we observed a strong correlation between phosphorylated PAK4S474, which represents PAK4 activity, and phosphorylated THS40, which reflects their enzymatic activity. Our findings suggest that targeting the PAK4 signaling pathways to restore dopamine levels may provide a new therapeutic approach in PD.

키워드

과제정보

This work was supported by a National Research Foundation of Korea (NRF) grant funded by the Korean government (Ministry of Science, ICT and Future Planning; 2017R1A2B3005714, 2017R1C-1B2006193, 2020R1A5A2017476).

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