Differential expression of RET and GDNF family receptor, GFR-α1, between striatum and substantia nigra following nigrostriatal lesion: A case for diminished GDNF-signaling

Authors

Ella A. Kasanga, Department of Pharmacology & Neuroscience, Center for Healthy Aging, Department of Pharmacology & Neuroscience, University of North Texas Health Science Center, Fort Worth, TX 76107, USA.
Yoonhee Han, Department of Environmental Health Sciences, Robert Stempel School of Public Health & Social Work, Florida International University, Miami, FL 33199, USA.
Walter Navarrete, Department of Pharmacology & Neuroscience, Center for Healthy Aging, Department of Pharmacology & Neuroscience, University of North Texas Health Science Center, Fort Worth, TX 76107, USA.
Robert McManus, Department of Pharmacology & Neuroscience, Center for Healthy Aging, Department of Pharmacology & Neuroscience, University of North Texas Health Science Center, Fort Worth, TX 76107, USA.
Marla K. Shifflet, Department of Pharmacology & Neuroscience, Center for Healthy Aging, Department of Pharmacology & Neuroscience, University of North Texas Health Science Center, Fort Worth, TX 76107, USA.
Caleb Parry, Department of Pharmacology & Neuroscience, Center for Healthy Aging, Department of Pharmacology & Neuroscience, University of North Texas Health Science Center, Fort Worth, TX 76107, USA.
Arturo Barahona, Department of Environmental Health Sciences, Robert Stempel School of Public Health & Social Work, Florida International University, Miami, FL 33199, USA.
Fredric P. Manfredsson, Parkinson's Disease Research Unit, Department of Translational Neuroscience, Barrow Neurological Institute, Phoenix, AZ 85013, USA.Follow
Vicki A. Nejtek, Department of Pharmacology & Neuroscience, Center for Healthy Aging, Department of Pharmacology & Neuroscience, University of North Texas Health Science Center, Fort Worth, TX 76107, USA.
Jason R. Richardson, Department of Environmental Health Sciences, Robert Stempel School of Public Health & Social Work, Florida International University, Miami, FL 33199, USA.
Michael F. Salvatore, Department of Pharmacology & Neuroscience, Center for Healthy Aging, Department of Pharmacology & Neuroscience, University of North Texas Health Science Center, Fort Worth, TX 76107, USA. Electronic address: Michael.Salvatore@unthsc.edu.

Document Type

Article

Abstract

Although glial cell line-derived neurotrophic factor (GDNF) showed efficacy in preclinical and early clinical studies to alleviate parkinsonian signs in Parkinson's disease (PD), later trials did not meet primary endpoints, giving pause to consider further investigation. While GDNF dose and delivery methods may have contributed to diminished efficacy, one crucial aspect of these clinical studies is that GDNF treatment began ∼8 years after PD diagnosis; a time point representing several years after near 100% depletion of nigrostriatal dopamine markers in striatum and at least 50% in substantia nigra (SN), which represents a time point of initiating GDNF treatment later than reported in some preclinical studies. With nigrostriatal terminal loss exceeding 70% at PD diagnosis, we utilized hemiparkinsonian rats to determine if expression of GDNF family receptor, GFR-α1, and receptor tyrosine kinase, RET, differed between striatum and SN at 1 and 4 weeks following a 6-hydroxydopamine (6-OHDA) hemilesion. Whereas GDNF expression changed minimally, GFR-α1 expression decreased progressively in striatum and in tyrosine hydroxylase positive (TH+) cells in SN, correlating with reduced TH cell number. However, in nigral astrocytes, GFR-α1 expression increased. RET expression decreased maximally in striatum by 1 week, whereas in the SN, a transient bilateral increase occurred, returning to control levels by 4 weeks. Expression of brain-derived neurotrophic factor (BDNF) or its receptor, TrkB, were unchanged throughout lesion progression. Together, these results reveal that differential GFR-α1 and RET expression between the striatum and SN, and cell-specific differences in GFR-α1 expression in SN, occur during nigrostriatal neuron loss. Targeting loss of GDNF receptors thus appears critical to enhance GDNF therapeutic efficacy against nigrostriatal neuron loss. SIGNIFICANCE STATEMENT: Although preclinical evidence supports that GDNF provides neuroprotection and improves locomotor function in preclinical studies, there is uncertainty if it can alleviate motor impairment in Parkinson's disease patients. Using the established 6-OHDA hemiparkinsonian rat model, we determined whether expression of its cognate receptors, GFR-α1 and RET, were differentially affected between striatum and substantia nigra in a timeline study. In striatum, there was early and significant loss of RET, but a gradual, progressive loss of GFR-α1. In contrast, RET transiently increased in lesioned substantia nigra, but GFR-α1 progressively decreased only in nigrostriatal neurons and correlated with TH cell loss. Our results indicate that direct availability of GFR-α1 may be a critical element that determines GDNF efficacy following striatal delivery.

Keywords

6-hydroxydopamine, nigrostriatal, BDNF, GDNF, GFR-α1, Neuroprotection, Parkinson's disease, RET

Publication Date

5-12-2023

Publication Title

Experimental neurology

E-ISSN

1090-2430

Volume

366

First Page

114435

PubMed ID

37178997

Digital Object Identifier (DOI)

10.1016/j.expneurol.2023.114435

Recommended Citation

Kasanga, Ella A.; Han, Yoonhee; Navarrete, Walter; McManus, Robert; Shifflet, Marla K.; Parry, Caleb; Barahona, Arturo; Manfredsson, Fredric P.; Nejtek, Vicki A.; Richardson, Jason R.; and Salvatore, Michael F., "Differential expression of RET and GDNF family receptor, GFR-α1, between striatum and substantia nigra following nigrostriatal lesion: A case for diminished GDNF-signaling" (2023). Translational Neuroscience. 2248.
https://scholar.barrowneuro.org/neurobiology/2248