Nigral-specific increase in ser31 phosphorylation compensates for tyrosine hydroxylase protein and nigrostriatal neuron loss: Implications for delaying parkinsonian signs

Ella A. Kasanga, Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, TX 76117, USA.
Yoonhee Han, Robert Stempel School of Public Health and Social Work, Florida International University, Miami, FL 33199, USA.
Marla K. Shifflet, Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, TX 76117, USA.
Walter Navarrete, Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, TX 76117, USA.
Robert McManus, Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, TX 76117, USA.
Caleb Parry, Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, TX 76117, USA.
Arturo Barahona, Robert Stempel School of Public Health and Social Work, Florida International University, Miami, FL 33199, USA.
Vicki A. Nejtek, Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, TX 76117, USA.
Fredric P. Manfredsson, Parkinson's Disease Research Unit, Department of Translational Neuroscience, Barrow Neurological Institute, Phoenix, AZ 85013, USA.Follow
Jeffrey H. Kordower, ASU-Banner Neurodegenerative Disease Research Center, Arizona State University, Tempe, AZ 85287, USA.
Jason R. Richardson, Robert Stempel School of Public Health and Social Work, Florida International University, Miami, FL 33199, USA.
Michael F. Salvatore, Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, TX 76117, USA. Electronic address: michael.salvatore@unthsc.edu.

Document Type

Article

Abstract

Compensatory mechanisms that augment dopamine (DA) signaling are thought to mitigate onset of hypokinesia prior to major loss of tyrosine hydroxylase (TH) in striatum that occurs in Parkinson's disease. However, the identity of such mechanisms remains elusive. In the present study, the rat nigrostriatal pathway was unilaterally-lesioned with 6-hydroxydopamine (6-OHDA) to determine whether differences in DA content, TH protein, TH phosphorylation, or D receptor expression in striatum or substantia nigra (SN) aligned with hypokinesia onset and severity at two time points. In striatum, DA and TH loss reached its maximum (>90%) 7 days after lesion induction. However, in SN, no DA loss occurred, despite ∼60% TH loss. Hypokinesia was established at 21 days post-lesion and maintained at 28 days. At this time, DA loss was ∼60% in the SN, but still of lesser magnitude than TH loss. At day 7 and 28, ser31 TH phosphorylation increased only in SN, corresponding to less DA versus TH protein loss. In contrast, ser40 TH phosphorylation was unaffected in either region. Despite DA loss in both regions at day 28, D receptor expression increased only in lesioned SN. These results support the concept that augmented components of DA signaling in the SN, through increased ser31 TH phosphorylation and D receptor expression, contribute as compensatory mechanisms against progressive nigrostriatal neuron and TH protein loss, and may mitigate hypokinesia severity.

Keywords

Bradykinesia, Dopamine, Hypokinesia, Parkinson's disease, Parkinsonism, Prodromal, Striatum, Substantia nigra, Tyrosine hydroxylase, ser31 phosphorylation

Medical Subject Headings

Animals; Rats; Phosphorylation; Tyrosine 3-Monooxygenase; Hypokinesia; Dopamine; Neurons; Oxidopamine (toxicity); Substantia Nigra

Publication Date

10-1-2023

Publication Title

Experimental neurology

E-ISSN

1090-2430

Volume

368

First Page

114509

PubMed ID

37634696

Digital Object Identifier (DOI)

10.1016/j.expneurol.2023.114509

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