Differential Effects of Glial Cell Line‐Derived Neurotrophic Factor and Neurturin on Developing and Adult Substantia Nigra Dopaminergic Neurons

Abstract

Neurturin (NTN) and glial cell line-derived neurotrophic factor (GDNF), two members of the GDNF family of growth factors, exert very similar biological activities in different systems, including the substantia nigra. Our goal in the present work was to compare their function and define whether nonoverlapping biological activities on midbrain dopaminergic neurons exist. We first found that NTN and GDNF are differentially regulated during postnatal development. NTN mRNA progressively decreased in the ventral mesencephalon and progressively increased in the striatum, coincident with a decrease in GDNF mRNA expression. This finding suggested distinct physiological roles for each factor in the nigrostriatal system. We therefore examined their function in ventral mesencephalon cultures and found that NTN promoted survival comparable with GDNF, but only GDNF induced sprouting and hypertrophy of developing dopaminergic neurons. We subsequently examined the ability of NTN to prevent the 6-hydroxydopamine-induced degeneration of adult dopaminergic neurons in vivo. Fibroblasts genetically engineered to deliver high levels of GDNF or NTN were grafted supranigrally. NTN was found to be as potent as GDNF at preventing the death of nigral dopaminergic neurons, but only GDNF induced tyrosine hydroxylase staining, sprouting, or hypertrophy of dopaminergic neurons. In conclusion, our results show selective survival-promoting effects of NTN over wider survival, neuritogenic, and hypertrophic effects of GDNF on dopaminergic neurons in vitro and in vivo. Such differences are likely to underlie unique roles for each factor in postnatal development and may ultimately be exploited in the treatment of Parkinson's disease.

Valproate protects dopaminergic neurons in midbrain neuron/glia cultures by stimulating the release of neurotrophic factors from astrocytes

“…VPA upregulate GDNF and BDNF expression in astrocytes GDNF has been shown to promote DA neurons survival, induce neurite outgrowth and sprouting, [31][32][33] upregulate TH expression and enhance synaptic efficacy. 34 The presence of GDNF messenger RNA (mRNA) in the astrocytes of substantia nigra, 35,36 and the high sensitivity of DA neurons to this neurotrophin make GDNF a likely candidate for the yet unidentified VPA-induced, astrocytes-secreted neurotrophic substance.…”

The effects of docosahexaenoic acid on glial derived neurotrophic factor and neurturin in bilateral rat model of Parkinson's disease.

“…Neurotrophic factors regulate many critical aspects of the ontogeny of neurons, such as promoting survival, neurite branching and synaptogenesis [23]. One of those neurotrophic factors is GDNF which promotes the survival of the embryonic dopaminergic neurons of the midbrain during PD [24].…”

Delayed delivery of AAV-GDNF prevents nigral neurodegeneration and promotes functional recovery in a rat model of Parkinson's disease

“…In addition, another possibility is to suggest that further functional recovery of lesioned nigrostriatal pathways is not obtained by GDNF alone, and that other neurotrophic factors such as neurturin or artemin, another member of GDNF family with strong homology to GDNF, may be necessary. [35][36][37] In conclusion, we have shown that (1) AAV vectormediated GDNF gene delivery in the striatum promoted the survival of DA neurons in the SN, increased the density of TH-IR fibers, and ameliorated behavioral and biochemical deficits even after the degenerative process had begun; (2) GDNFflag fusion protein was detected in the SN, suggesting the transgene-derived GDNF was retrogradely transported from the striatum to DA cell bodies in the SN, while maintaining functional connections within the nigrostriatal pathway. These data indicate that AAV-mediated GDNF gene delivery in the striatum is feasible as a neuroprotective gene therapy of PD.…”