Expression of GDNF receptors GFRα1 and RET is preserved in substantia nigra pars compacta of aging Asian Indians

Abstract

Glial derived neurotrophic factor (GDNF) protects dopaminergic nigral neurons and may prevent the progression of age-related motor deficits and Parkinson's disease. The multi-component receptor complex which mediates the neuroprotective action of GDNF comprises of GDNF receptor alpha1 (GFRα1), a ligand binding cell surface component and RET receptor tyrosine kinase (RET) the signaling component. The expression of both these receptors in the normally aging human substantia nigra pars compacta (SNpc) needs to be studied since GDNF infusion is being considered for restoration of the lost nigrostriatal function. In the present study, we used unbiased stereology to quantify the number of GFRα1 and RET immunoreactive neurons in human SNpc from 28 weeks of gestation to 88 years (n = 31). We further determined the levels of immunostaining intensity using densitometric image analysis to measure changes in levels of receptor expression. Here we report that human nigral dopaminergic neurons express GFRα1 and RET receptors at all ages. There was no reduction in the number of neurons expressing these receptors as a function of age. Moreover, there was no age-related decline in immunostaining intensity of both these receptors. It is likely that preservation of GDNF receptors in the nigral neurons is because these receptors are constitutively expressed in the human SNpc and thus it is GDNF responsive thru aging. The sustained receptor protein expression could also be another marker of preserved nigrostriatal function in Asian Indians. The latter possibility explains our earlier observation that the melanized nigral neurons are preserved with age in the Asian Indians.