Title

GFR-α1 Expression in Substantia Nigra Increases Bilaterally Following Unilateral Striatal GDNF in Aged Rats and Attenuates Nigral Tyrosine Hydroxylase Loss Following 6-OHDA Nigrostriatal Lesion

Authors

Ella A. Kasanga, Institute for Healthy Aging , University of North Texas Health Science Center , Fort Worth , Texas 76107 , United States.
Catherine L. Owens, Department of Pharmacology, Toxicology, & Neuroscience , Louisiana State University Health Sciences Center , Shreveport , Louisiana 71130 , United States.
Mark A. Cantu, Institute for Healthy Aging , University of North Texas Health Science Center , Fort Worth , Texas 76107 , United States.
Adam D. Richard, Department of Pharmacology, Toxicology, & Neuroscience , Louisiana State University Health Sciences Center , Shreveport , Louisiana 71130 , United States.
Richard W. Davis, Department of Pharmacology, Toxicology, & Neuroscience , Louisiana State University Health Sciences Center , Shreveport , Louisiana 71130 , United States.
Lisa M. McDivitt, Department of Pharmacology, Toxicology, & Neuroscience , Louisiana State University Health Sciences Center , Shreveport , Louisiana 71130 , United States.
Blake Blancher, Department of Pharmacology, Toxicology, & Neuroscience , Louisiana State University Health Sciences Center , Shreveport , Louisiana 71130 , United States.
Brandon S. Pruett, Department of Pharmacology, Toxicology, & Neuroscience , Louisiana State University Health Sciences Center , Shreveport , Louisiana 71130 , United States.
Christopher Tan, Institute for Healthy Aging , University of North Texas Health Science Center , Fort Worth , Texas 76107 , United States.
Austin Gajewski, Institute for Healthy Aging , University of North Texas Health Science Center , Fort Worth , Texas 76107 , United States.
Fredric P. Manfredsson, Parkinson's Disease Research Unit, Department of Neurobiology , Barrow Neurological Institute , Phoenix , Arizona 85013 , United States.
Vicki A. Nejtek, Institute for Healthy Aging , University of North Texas Health Science Center , Fort Worth , Texas 76107 , United States.
Michael F. Salvatore, Institute for Healthy Aging , University of North Texas Health Science Center , Fort Worth , Texas 76107 , United States.

Document Type

Article

Abstract

Glial cell line-derived neurotrophic factor (GDNF) improved motor function in Parkinson's disease (PD) patients in Phase I clinical trials, and these effects persisted months after GDNF discontinuation. Conversely, phase II clinical trials reported no significant effects on motor improvement vs placebo. The disease duration and the quantity, infusion approach, and duration of GDNF delivery may affect GDNF efficacy in PD treatment. However, identifying mechanisms activated by GDNF that affect nigrostriatal function may reveal additional avenues to partially restore nigrostriatal function. In PD and aging models, GDNF affects tyrosine hydroxylase (TH) expression or phosphorylation in substantia nigra (SN), long after a single GDNF injection in striatum. In aged rats, the GDNF family receptor, GFR-α1, increases TH expression and phosphorylation in SN. To determine if GFR-α1 could be a mechanistic link in long-term GDNF impact, we conducted two studies; first to determine if a single unilateral striatal delivery of GDNF affected GFR-α1 and TH over time (1 day, 1 week, and 4 weeks) in the striatum or SN in aged rats, and second, to determine if soluble GFR-α1 could mitigate TH loss following 6-hydroxydopamine (6-OHDA) lesion. In aged rats, GDNF bilaterally increased ser31 TH phosphorylation and GFR-α1 expression in SN at 1 day and 4 weeks after GDNF, respectively. In striatum, GFR-α1 expression decreased 1 week after GDNF, only on the GDNF-injected side. In 6-OHDA-lesioned rats, recombinant soluble GFR-α1 mitigated nigral, but not striatal, TH protein loss following 6-OHDA. Together, these results show GDNF has immediate and long-term impact on dopamine regulation in the SN, which includes a gradual increase in GFR-α1 expression that may sustain TH expression and dopamine function therein.

Keywords

6-hydroxydopamine, Parkinson’s disease, Substantia nigra, aging, nigrostriatal, tyrosine hydroxylase

Medical Subject Headings

Aging (metabolism); Animals; Dopamine (metabolism); Glial Cell Line-Derived Neurotrophic Factor (pharmacology); Glial Cell Line-Derived Neurotrophic Factor Receptors (metabolism); Neurons (drug effects, metabolism); Oxidopamine (toxicity); Phosphorylation (drug effects); Rats; Substantia Nigra (drug effects, metabolism); Tyrosine 3-Monooxygenase (metabolism)

Publication Date

10-16-2019

Publication Title

ACS chemical neuroscience

E-ISSN

1948-7193

Volume

10

Issue

10

First Page

4237

Last Page

4249

PubMed ID

31538765

Digital Object Identifier (DOI)

10.1021/acschemneuro.9b00291

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