Age‐associated decrease in GDNF and its cognate receptor GFRα‐1 protein expression in human skin

Abstract

Glial cell line-derived neurotrophic factor (GDNF) and its cognate receptor (GFRα-1) are expressed in normal human skin. They are involved in murine hair follicle morphogenesis and cycling control. We hypothesize that 'GDNF and GFRα-1 protein expression in human skin undergoes age-associated alterations. To test our hypothesis, the expression of these proteins was examined in human skin specimens obtained from 30 healthy individuals representing three age groups: children (5-18 years), adults (19-60 years) and the elderly (61-81 years). Immunofluorescent and light microscopic immunohistologic analyses were performed using tyramide signal amplification and avidin-biotin complex staining methods respectively. GDNF mRNA expression was examined by RT-PCR analysis. GDNF mRNA and protein as well as GFRα-1 protein expressions were detected in normal human skin. We found significantly reduced epidermal expression of these proteins with ageing. In the epidermis, the expression was strong in the skin of children and declined gradually with ageing, being moderate in adults and weak in the elderly. In children and adults, the expression of both GDNF and GFRα-1 proteins was strongest in the stratum basale and decreased gradually towards the surface layers where it was completely absent in the stratum corneum. In the elderly, GDNF and GFRα-1 protein expression was confined to the stratum basale. In the dermis, both GDNF and GFRα-1 proteins had strong expressions in the fibroblasts, sweat glands, sebaceous glands, hair follicles and blood vessels regardless of the age. Thus there is a decrease in epidermal GDNF and GFRα-1 protein expression in normal human skin with ageing. Our findings suggest that the consequences of this is that GFRα-1-mediated signalling is altered during the ageing process. The clinical and therapeutic ramifications of these observations mandate further investigations.

The Role of Alpha-Synuclein Autoantibodies in the Induction of Brain Inflammation and Neurodegeneration in Aged Humans

“…Brain reactive antigens, autoantibodies, and their link to FcγRmediated microglial cells activation, pro-inflammatory cytokines, (e.g., IL-1β, IL6, IL18, and TNFα) production, neurons death, and the memory and learning defects have been observed in several neurological diseases (Polinsky et al, 1991;Ulvestad et al, 1994a,b;Terryberry et al, 1998;Gruden et al, 2007;Vyshkina and Kalman, 2008;Okun et al, 2010;Lunnon et al, 2011;Cribbs et al, 2012;Satoh et al, 2012;Vacirca et al, 2012;Joachim et al, 2013;Kam et al, 2013;Murinello et al, 2014;Paris et al, 2014;Schweig et al, 2017Schweig et al, , 2019Yang et al, 2019). The number of the growth and neurotrophic factors, i.e., brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), and the glial cell linederived neurotrophic factor (GDNF) are essential for pruning, myelination, differentiation, synaptic and neuronal growth, survival of neurons, and the scalp skin homeostasis (Huang and Reichardt, 2001;Skoff et al, 2003;Adly et al, 2006Adly et al, , 2016Caldeira et al, 2007;Skaper, 2012;Mitra et al, 2021). Studies have shown the link between the abnormal brain formation of BDNF, NGF, and GDNF and the neurodegeneration that comes with age-related brain diseases (Grassi-Oliveira et al, 2008;Komulainen et al, 2008;Numakawa et al, 2018;Lima Giacobbo et al, 2019).…”