PTN
Pleiotrophin precursor (PTN) (Heparin-binding brain mitogen) (HBBM) (Heparin-binding growth factor 8) (HBGF-8) (Heparin-binding growth-associated molecule) (HB-GAM) (Heparin-binding neurite outgrowth-promoting factor) (HBNF) (Heparin-binding neurite outgrowth-promoting factor 1) (HBNF-1) (Osteoblast-specific factor 1) (OSF-1) [HBNF1] [NEGF1]
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Inflammation is a common factor of pathologies such as obesity, type 2 diabetes or neurodegenerative diseases. Chronic inflammation is considered part of the pathogenic mechanisms of different disorders associated with aging. Interestingly, peripheral inflammation and the associated metabolic alterations not only facilitate insulin resistance and diabetes but also neurodegenerative disorders. Therefore, the identification of novel pathways, common to the development of these diseases, which modulate the immune response and signaling is key. It will provide highly relevant information to advance our knowledge of the multifactorial process of aging, and to establish new biomarkers and/or therapeutic targets to counteract the underlying chronic inflammatory processes. One novel pathway that regulates peripheral and central immune responses is triggered by the cytokines pleiotrophin (PTN) and midkine (MK), which bind its receptor, Receptor Protein Tyrosine Phosphatase (RPTP) β/ζ, and inactivate its phosphatase activity. In this review, we compile a growing body of knowledge suggesting that PTN and MK modulate the immune response and/or inflammation in different pathologies characterized by peripheral inflammation associated with insulin resistance, such as aging, and in central disorders characterized by overt neuroinflammation, such as neurodegenerative diseases and endotoxemia. Evidence strongly suggests that regulation of the PTN and MK signaling pathways may provide new therapeutic opportunities particularly in those neurological disorders characterized by increased PTN and/or MK cerebral levels and neuroinflammation. Importantly, we discuss existing therapeutics, and others being developed, that modulate these signaling pathways, and their potential use in pathologies characterized by overt neuroinflammation.
Keywords
- PTPRZ
- aging
- inflammation
- midkine
- neurodegeneration
- neuroinflammation
- obesity
- pleiotrophin
The cerebellum is a structure of the central nervous system involved in balance, motor coordination, and voluntary movements. The elementary circuit implicated in the control of locomotion involves Purkinje cells, which receive excitatory inputs from parallel and climbing fibers, and are regulated by cerebellar interneurons. In mice as in human, the cerebellar cortex completes its development mainly after birth with the migration, differentiation, and synaptogenesis of granule cells. These cellular events are under the control of numerous extracellular matrix molecules including pleiotrophin (PTN). This cytokine has been shown to regulate the morphogenesis of Purkinje cells ex vivo and in vivo via its receptor PTPζ. Since Purkinje cells are the unique output of the cerebellar cortex, we explored the consequences of their PTN-induced atrophy on the function of the cerebellar neuronal circuit in mice. Behavioral experiments revealed that, despite a normal overall development, PTN-treated mice present a delay in the maturation of their flexion reflex. Moreover, patch clamp recording of Purkinje cells revealed a significant increase in the frequency of spontaneous excitatory postsynaptic currents in PTN-treated mice, associated with a decrease of climbing fiber innervations and an abnormal perisomatic localization of the parallel fiber contacts. At adulthood, PTN-treated mice exhibit coordination impairment on the rotarod test associated with an alteration of the synchronization gait. Altogether these histological, electrophysiological, and behavior data reveal that an early ECM disruption of PTN composition induces short- and long-term defaults in the establishment of proper functional cerebellar circuit.
MeSH Terms
- Aging
- Animals
- Carrier Proteins
- Cell Shape
- Cerebellum
- Cytokines
- Excitatory Postsynaptic Potentials
- Extracellular Space
- Female
- Gait
- Humans
- Locomotion
- Male
- Mice
- Nerve Net
- Neurons
Keywords
- Cerebellum
- Locomotor behavior
- Neurodevelopment
- Pleiotrophin
- Purkinje cells
This review highlights the significance of protein tyrosine nitration (PTN) in signal transduction pathways, the progress achieved in analytical methods, and the implication of nitration in the cellular pathophysiology of aging and age-related neurodegenerative diseases. Although mass spectrometry of nitrated peptides has become a powerful tool for the characterization of nitrated peptides, the low stoichiometry of this modification clearly necessitates the use of affinity chromatography to enrich modified peptides. Analysis of nitropeptides involves identification of endogenous, intact modification as well as chemical conversion of the nitro group to a chemically reactive amine group and further modifications that enable affinity capture and enhance detectability by altering molecular properties. In this review, we focus on the recent progress in chemical derivatization of nitropeptides for enrichment and mass analysis, and for detection and quantification using various analytical tools. PTN participates in physiological processes, such as aging and neurodegenerative diseases. Accumulation of 3-nitrotyrosine has been found to occur during the aging process; this was identified through mass spectrometry. Further, there are several studies implicating the presence of nitrated tyrosine in age-related diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis.
MeSH Terms
- Aging
- Amino Acid Sequence
- Chromatography, Affinity
- Humans
- Mass Spectrometry
- Molecular Sequence Data
- Neurodegenerative Diseases
- Peptide Fragments
- Proteins
- Reactive Nitrogen Species
- Tyrosine
Keywords
- 3-nitrotyrosine
- aging
- neurodegeneration
- protein tyrosine nitration
- reactive nitrogen species
Pleiotrophin (PTN) is a heparin-binding growth factor involved in angiogenesis during development and tumor growth. Plasmid therapy with PTN also induces angiogenesis after myocardial infarction. During aging, angiogenesis is impaired and we therefore examined whether a growth factor therapy with PTN is able to restore neovascularization. We evaluated the PTN effects on capillary-like endothelial sprouting in adult (n = 10) and senescent (n = 10) rats, using an ex vivo model of explanted aortic segments in culture. Freshly cut thoracic aortic rings from 3 and 24 month old (mo) rats (both n = 12) were cultured in a 3-dimensional collagen matrix with or without addition of recombinant human PTN (2.5-250 ng/ml) or Vascular Endothelial Growth Factor-165 (VEGF) (1-100 ng/ml) and the length of developed capillary network was quantified at day 3 and 6 by image analysis. After 6 days of culture, capillary-like tube formation was lower in control conditions in 24 mo aortic rings than in 3 mo rings. Addition of PTN increased dose-dependently the length of capillary-like tube formation in both 3 and 24 mo rings (P < 0.001 and P < 0.001 respectively). Age-associated impairment of capillary-like tube formation had been successfully restored in senescent aortic segments by PTN treatment. PTN induced development of capillary network similar to that observed with VEGF therapy with doses equal or superior to 10 ng/ml. PTN is able to induce ex vivo angiogenesis during aging and might be a new promising therapy to induce neovascularization in aged tissues as well as after age-associated cardiac, hindlimb or cerebral ischemia.
MeSH Terms
- Aging
- Animals
- Aorta
- Carrier Proteins
- Cytokines
- Humans
- In Vitro Techniques
- Male
- Neovascularization, Physiologic
- Rats
- Rats, Wistar
- Vascular Endothelial Growth Factor A