cAMP Response Element-Binding Protein- and Phosphorylation-Dependent Regulation of Tyrosine Hydroxylase by PAK4: Implications for Dopamine Replacement Therapy

So Yoon Won, Soon Tae You, Seung Won Choi, Catriona McLean, Eun Young Shin, Eung Gook Kim

Research output: Contribution to journalArticleResearchpeer-review

3 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)493-499
Number of pages7
JournalMolecules and Cells
Volume44
Issue number7
DOIs
Publication statusPublished - 2021
Externally publishedYes

Keywords

  • Dopamine
  • PAK4
  • Parkinson’s disease
  • Post-treatment
  • Tyrosine hydroxylase

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