Polysialylated neuronal cell adhesion molecule (PSA-NCAM), a polysialylated protein constitutively expressed in the hippocampus, is involved in neuronal growth, synaptic plasticity and neurotrophin signaling. In particular, PSA-NCAM mediates Ret-independent glial-derived neurotrophic factor (GDNF) signaling, leading to downstream FAK activation. GDNF has potent seizure-suppressant action, whereas PSA-NCAM is upregulated by seizure activity. However, the involvement of Ret-independent GDNF signaling in temporal lobe epilepsy (TLE) is not established. We tested the effects of PSA-NCAM inactivation on neurodegeneration and epileptogenesis in a mouse model of TLE. In this model, unilateral intrahippocampal kainic acid (KA) injection induced degeneration of CA1, CA3c and hilar neurons, followed by spontaneous recurrent focal seizures. In the contralateral, morphologically preserved hippocampus, a long-lasting increase of PSA-NCAM immunoreactivity was observed. Inactivation of PSA-NCAM by endoneuraminidase (EndoN) administration into the contralateral ventricle of KA-treated mice caused severe degeneration of CA3a,b neurons and dentate gyrus granule cells in the epileptic focus, and led to early onset of focal seizures. This striking trans-hemispheric alteration suggested that PSA-NCAM mediates GDNF signaling, leading to transport of neuroprotective signals into the lesioned hippocampus. This hypothesis was confirmed by injecting GDNF antibodies into the contralateral hippocampus of KA-treated mice, thereby reproducing the enhanced neurodegeneration seen after PSA-NCAM inactivation. Furthermore, contralateral EndoN and anti-GDNF treatment decreased GDNF family receptor alpha1 immunoreactivity and FAK phosphorylation in the epileptic focus. Thus, Ret-independent GDNF signaling across the commissural projection might protect CA3a,b neurons and delay seizure onset. These findings implicate GDNF in the control of epileptogenesis and offer a possible mechanism explaining lesion asymmetry in mesial TLE.
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http://dx.doi.org/10.1111/j.1460-9568.2010.07272.x | DOI Listing |
Curr Cardiol Rev
January 2025
Department of Pharmacology, All India Institute of Medical Sciences, Jodhpur, Rajasthan, 342005, India.
Cardiovascular-kidney-metabolic (CKM) syndrome is the association between obesity, diabetes, CKD (chronic kidney disease), and cardiovascular disease. GDF-15 mainly acts through the GFRAL (Glial cell line-derived neurotrophic factor Family Receptor Alpha-Like) receptor. GDF-15 and GDFRAL complex act mainly through RET co-receptors, further activating Ras and phosphatidylinositol-3-kinase (PI3K)/Akt pathways through downstream signaling.
View Article and Find Full Text PDFKidney explant cultures are traditionally carried out at air-liquid interfaces, which disrupts 3D tissue structure and limits interpretation of developmental data. To overcome this limitation, we developed a 3D culture technique using hydrogel embedding to capture morphogenesis in real time. We show that 3D culture better approximates -like niche spacing and dynamic tubule tip rearrangement, as well as -like presentation of branching defects under perturbations to glial cell-derived neurotrophic factor (GDNF)- RE arranged during T ransfection (RET) tyrosine kinase signaling.
View Article and Find Full Text PDFEndocr Relat Cancer
January 2025
C Alvarez, Centro de Investigación en Medicina Molecular y Enfermedades Crónicas (CIMUS), University of Santiago de Compostela (USC), Santiago de Compostela, Spain.
The discovery of RET mutations in Multiple Endocrine Neoplasia 2A (MEN2A) in 1993 ignited a revolution in our understanding of this versatile receptor. Since then, RET's influence has expanded to encompass diverse organs, including the pituitary gland. This review explores the multifaceted role of RET in somatotrophs, focusing on two opposing pathways: proliferation versus differentiation and apoptosis.
View Article and Find Full Text PDFArch Toxicol
December 2024
Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
Exposure to diesel exhaust is associated with increased risk of cardiovascular and lung disease. Substituting petroleum diesel with renewable diesel can alter emission properties but the potential health effects remain unclear. This study aimed to explore toxicity and underlying mechanisms of diesel exhaust from renewable fuels.
View Article and Find Full Text PDFNat Commun
December 2024
Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.
Growth differentiation factor 15, GDF15, and glucagon-like peptide-1 (GLP-1) analogues act through brainstem neurons that co-localise their receptors, GDNF-family receptor α-like (GFRAL) and GLP1R, to reduce food intake and body weight. However, their use as clinical treatments is partially hampered since both can also induce sickness-like behaviours, including aversion, that are mediated through a well-characterised pathway via the exterolateral parabrachial nucleus. Here, in mice, we describe a separate pathway downstream of GFRAL/GLP1R neurons that involves a distinct population of brain-derived neurotrophic factor (BDNF) cells in the medial nucleus of the tractus solitarius.
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