In Vivo Protection of Nigral Dopamine Neurons by Lentiviral Gene Transfer of the Novel GDNF-Family Member Neublastin/Artemin

The Candidate Neuroprotective Agent Artemin Induces Autonomic Neural Dysplasia without Preventing Peripheral Nerve Dysfunction

“…The high affinity ART receptor is clearly GFRα-3, but neither a competing laboratory (Masure et al, 1999) nor our data (Figures 4, 5) corroborate a proposed low affinity ART-GFRα-1 pairing Milbrandt et al, 1998). However, it cannot be ruled out that supraphysiological ART concentrations might mediate productive signaling through other GFRα receptors, a possibility supported by the upregulation of ART in rat striatum ipsilateral to a chemical lesion (Zhou et al, 2000) and the capacity of ART gene therapy to ameliorate chemical lesions to mesencephalic dopaminergic neurons (Rosenblad et al, 2000) despite very low levels (Stover et al, 2000) or absence (Naveilhan et al, 1998;Widenfalk et al, 1998) of GFRα-3 expression at this site. Further work is needed to resolve this question.…”

“…At the amino acid level, the homology between these two molecules was 77%. During our characterization of Grnf4, the protein was described by three independent labs as ART , enovin (Masure et al, 1999) and neublastin (Rosenblad et al, 2000). Our human GRNF4 and mouse Grnf4 clones were identical to the published ART sequences for the gene and protein.…”

“…Rather, it likely reflects an absence of Art involvement in regeneration of somatic nerves in adult animals (Hoke et al, 2000). DISCUSSION ART Masure et al, 1999), the principal ligand of GFRα-3, supports neuron survival in many autonomic and sensory ganglia in the PNS as well as certain populations in the CNS (Rosenblad et al, 2000). However, ART and GFRα-3 are minimally expressed in the CNS in vivo Masure et al, 1999), suggesting that this signaling pathway acts primarily to influence PNS development under normal physiological conditions.…”

“…One laboratory described a single 113 aa transcript ; another demonstrated a series of 5 splice variants, of which 2 pro-peptides can be processed to yield a single mature 113 aa peptide (Masure et al, 1999); while a third reported three splice variants of 113, 116, and 140 aa (Rosenblad et al, 2000). Our data support the presence of a single ART gene with three mature peptides (104, 106, and 113 aa) resulting from alternative cleavage of a single pro-peptide (Figure 3).…”

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.…”