GDNF signaling in subjects with minimal motor deficits and Parkinson's disease

• Published in: Neurobiology of disease Vol. 153; p. 105298
• Main Authors: Chu, Yaping, Kordower, Jeffrey H.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.06.2021; Elsevier
• Subjects: Aged; Aged, 80 and over; alpha-Synuclein - genetics; Animals; Animals, Genetically Modified; Brain - metabolism; Densitometry; Dopaminergic neurons; Female; Glial Cell Line-Derived Neurotrophic Factor - metabolism; Humans; Macaca fascicularis; Male; Neurturin - metabolism; Parkinson Disease - metabolism; Parkinson Disease - physiopathology; Parkinsonian Disorders - genetics; Parkinsonian Disorders - metabolism; Phosphorylated ribosomal protein S6; Prodromal Parkinson's disease; Prodromal Symptoms; Proto-Oncogene Proteins c-ret - metabolism; RET; Ribosomal Protein S6 - metabolism; Signal Transduction; RET; Dopaminergic neurons; Phosphorylated ribosomal protein S6; Prodromal Parkinson's disease
• ISSN: 0969-9961; 1095-953X; 1095-953X
• DOI: 10.1016/j.nbd.2021.105298

The failure of glial cell derived neurotropic factor to be efficacious in blinded clinical trials for Parkinson's disease may be due to alterations in signaling receptors and downstream signaling molecules. To test this hypothesis, brain sections were obtained from older adults with no motor deficit (n = 6), minimal motor deficits (n = 10), and clinical diagnosis of Parkinson's disease (n = 10) who underwent motor examination proximate to death. Quantitative unbiased stereology and densitometry were performed to analyze RET and phosphorylated ribosomal protein S6 expression in nigral neurons. Individuals with no motor deficit had extensive and intense RET and phosphorylated ribosomal protein S6 immunoreactive neurons in substantia nigra. The number and staining intensity of RET-immunoreactive neurons were reduced moderately in subjects with minimal motor deficits and severely reduced in Parkinson's disease relative to no motor deficit group. The number and staining intensity of phosphorylated ribosomal protein S6 was more markedly reduced in both subjects with minimal motor deficits and Parkinson's disease. Reductions in levels of RET and phosphorylated ribosomal protein S6 were recapitulated in a non-human primate genetic Parkinson's disease model based on over-expression of human mutant α-synuclein (A53T). These data indicate that for neurotrophic factors to be effective in patients with minimal motor deficits or PD, these factors would likely have to upregulate RET and phosphorylated ribosomal protein S6 immunoreactive neurons in substantia nigra . [Display omitted] •RET and p-rpS6 are continuously expressing in nigral neurons in normal aging.•Subjects with MMD have a slight decrease of RET and significant reduce of p-rpS6.•Subjects with PD display significant diminish of both RET and p-rpS6 expressions.•Dysfunction of GDNF signaling pathway begins early during the PD process.