Nitration and increased alpha-synuclein expression associated with dopaminergic neurodegeneration in equine pituitary pars intermedia dysfunction.
Abstract: Equine pituitary pars intermedia dysfunction (PPID) is a spontaneously occurring progressive disease affecting aged horses and ponies. The pathogenesis of PPID is poorly understood, but the available evidence supports a loss of dopaminergic inhibition of the melanotropes of the pars intermedia. Horses with PPID have increased plasma concentrations of pars intermedia pro-opiomelanocortin-derived peptides that decrease in response to dopamine or dopamine agonist administration. Dopamine and dopamine metabolite concentrations are decreased in the pars intermedia of affected horses compared to age-matched control horses. Horses with disease that are treated with the dopamine agonist pergolide show improvement in clinical signs and normalisation of diagnostic test results. In the present study, immunohistochemical evaluation of pituitary and hypothalamic tissue demonstrated reduced tyrosine hydroxylase immunoreactivity in affected horses compared to age-matched and young controls, supporting the role of dopaminergic neurodegeneration in PPID. In addition, immunohistochemical evaluation revealed an increase in the oxidative stress marker, 3-nitrotyrosine and in nerve terminal protein, alpha-synuclein that colocalised in the pars intermedia of horses with disease. These findings suggest a role for nitration of overexpressed alpha-synuclein in the pathogenesis of neurodegeneration in PPID.
Publication Date: 2005-03-31 PubMed ID: 15796757DOI: 10.1111/j.1365-2826.2005.01277.xGoogle Scholar: Lookup
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- Journal Article
- Research Support
- Non-U.S. Gov't
- Aging
- Biochemistry
- Diagnosis
- Disease Diagnosis
- Disease Etiology
- Dopamine
- Equine Diseases
- Equine Health
- Horses
- Immunohistochemistry
- Immunology
- Metabolism
- Neurodegenerative Disorders
- Neurological Diseases
- Oxidative Stress
- Pathogenesis
- Pathophysiology
- Peptides
- Physiology
- Pituitary Pars Intermedia Dysfunction
- Veterinary Research
Summary
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This research article explores the connection between certain biological markers and the disease known as equine pituitary pars intermedia dysfunction (PPID) – a prevalent disorder in aged horses. The researchers identify an increase in the specific markers, 3-nitrotyrosine and alpha-synuclein, alongside a decrease in dopaminergic activity as notably linked to the progression of PPID.
Background
The study investigates PPID, a disease in older horses characterized by various symptoms like loss of muscle mass, abnormal hair growth and others. While the exact cause of PPID is not well-understood, it is believed to be associated with a decline in the regulation activity of dopaminergic (associated with the neurotransmitter dopamine) cells of the pars intermedia – a part of the horse’s pituitary gland. This decrease in dopaminergic regulation correlates with augmenting peptide concentrations, resulting in the aforementioned symptoms. Treatment of PPID often includes administration of dopamine or dopamine agonists, which help normalize these peptide concentrations, alleviating some symptoms of the disease.
Method
To better understand the pathogenesis of PPID, the authors executed an immunohistochemical evaluation of pituitary and hypothalamic horse tissue, focusing particularly on the pars intermedia. This evaluation included age-matched and young control horses as well as horses with PPID.
- They focused on the level of activity of tyrosine hydroxylase, a primary enzyme responsible for dopamine production – reduced activity was observed in horses with PPID.
- They also looked at the concentrations of 3-nitrotyrosine, an oxidative stress marker, and alpha-synuclein, a nerve terminal protein. Both of these were found to be elevated in PPID-affected horses.
Findings
These findings offer insight into the pathogenesis of PPID. The reduced tyrosine hydroxylase activity confirmed the idea of a decreased dopaminergic activity being involved in PPID. More importantly, the increased presence of 3-nitrotyrosine and alpha-synuclein in the pars intermedia indicates these two factors’ role in the neurodegenerative aspect of PPID.
Implications
These results suggest a possible correlation between increased nitration of alpha-synuclein, triggered by higher levels of 3-nitrotyrosine, and the neurodegenerative aspect of PPID in horses. The study contributes to the scientific understanding of PPID and its underlying mechanisms, paving the way for potential new therapies targeting the observed abnormalities.
Cite This Article
APA
McFarlane D, Dybdal N, Donaldson MT, Miller L, Cribb AE.
(2005).
Nitration and increased alpha-synuclein expression associated with dopaminergic neurodegeneration in equine pituitary pars intermedia dysfunction.
J Neuroendocrinol, 17(2), 73-80.
https://doi.org/10.1111/j.1365-2826.2005.01277.x Publication
Researcher Affiliations
- Laboratory of Comparative Pharmacogenetics, Department of Biomedical Sciences, Atlantic Veterinary College, Charlottetown, PE, Canada. dmcfarlane@upei.ca
MeSH Terms
- Animals
- Blotting, Western
- Chronic Disease
- Dopamine / physiology
- Horse Diseases / metabolism
- Horse Diseases / pathology
- Horses
- Immunohistochemistry
- Nerve Degeneration / metabolism
- Nerve Degeneration / pathology
- Nerve Degeneration / veterinary
- Nerve Tissue Proteins / metabolism
- Nitrogen / metabolism
- Oxidative Stress
- Pituitary ACTH Hypersecretion / metabolism
- Pituitary ACTH Hypersecretion / pathology
- Pituitary ACTH Hypersecretion / veterinary
- Pituitary Gland / metabolism
- Pituitary Gland / pathology
- Synucleins
- Tyrosine / analogs & derivatives
- Tyrosine / metabolism
- Tyrosine 3-Monooxygenase / metabolism
- alpha-Synuclein
Citations
This article has been cited 19 times.- Vaikath N, Sudhakaran I, Abdi I, Gupta V, Majbour N, Ghanem S, Abdesselem H, Vekrellis K, El-Agnaf O. Structural and Biophysical Characterization of Stable Alpha-Synuclein Oligomers.. Int J Mol Sci 2022 Nov 23;23(23).
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- Tatum RC, McGowan CM, Dean RS, Ireland JL. Equine pituitary pars intermedia dysfunction: Identifying research priorities for diagnosis, treatment and prognosis through a priority setting partnership.. PLoS One 2021;16(1):e0244784.
- Horn R, Stewart AJ, Jackson KV, Dryburgh EL, Medina-Torres CE, Bertin FR. Clinical implications of using adrenocorticotropic hormone diagnostic cutoffs or reference intervals to diagnose pituitary pars intermedia dysfunction in mature horses.. J Vet Intern Med 2021 Jan;35(1):560-570.
- Fortin JS, Benskey MJ, Lookingland KJ, Patterson JS, Howey EB, Goudreau JL, Schott HC 2nd. Restoring pars intermedia dopamine concentrations and tyrosine hydroxylase expression levels with pergolide: evidence from horses with pituitary pars intermedia dysfunction.. BMC Vet Res 2020 Sep 25;16(1):356.
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