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

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 s...

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Bibliographic Details
Published in:Molecules and cells 2021, 44(7), , pp.493-499
Main Authors: Won, So-Yoon, You, Soon-Tae, Choi, Seung-Won, McLean, Catriona, Shin, Eun-Young, Kim, Eung-Gook
Format: Article
Language:English
Subjects:
Animals
Cyclic AMP Response Element-Binding Protein - metabolism
Dopamine - pharmacology
Dopamine - therapeutic use
Humans
p21-Activated Kinases - metabolism
Phosphorylation
Rats
Transfection
Tyrosine 3-Monooxygenase - metabolism
생물학
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Summary: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 S , which is essential for TH activation. Consistent with this result, in human midbrain tissues, we observed a strong correlation between phosphorylated PAK4 , which represents PAK4 activity, and phosphorylated TH , 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.
ISSN:1016-8478
0219-1032
DOI:10.14348/molcells.2021.2250