Intrastriatal grafting of a GDNF-producing cell line protects striatonigral neurons from quinolinic acid excitotoxicity in vivo.
Glial cell line-derived neurotrophic factor (GDNF) is a neurotrophic factor with a therapeutic potential in neurodegenerative disorders. GDNF is expressed in the adult striatum, but its signalling tyrosine kinase receptor, c-ret, has not been detected in this structure by in situ hybridization. In the present work, we first examined c-ret and GDNF receptor alpha 1 (GFR-alpha 1) expression using an RNAse protection assay, and found that both receptors are expressed in the adult rat striatum. We then examined whether GDNF was able to regulate the phenotype and/or prevent the degeneration of striatal projection neurons in a well-characterized model of excitotoxic damage. A fibroblast cell line, engineered to overexpress GDNF, was grafted in adult rats striatum 24 h before quinolinic acid (QUIN) injection. QUIN injection alone or in combination with the control cell line induced a loss of glutamic acid decarboxylase 67 (GAD)-, preprotachykinin A (PPTA)-, prodynorphin (DYN)- and preproenkephalin (PPE)-positive neurons. GDNF selectively prevented: (i) the loss of a subpopulation of striatonigral neurons expressing GAD and PPTA; (ii) the atrophy of PPTA-positive neurons; and (iii) the decrease in GAD, PPTA and DYN mRNA expression, after QUIN injection. Moreover, in unlesioned animals, GDNF increased the size of PPTA-positive neurons and up-regulated their mRNA levels. In contrast, GDNF showed no effect in intact or lesioned striatopallidal PPE-positive neurons. Thus, our findings show that GDNF selectively regulates the phenotype and protects striatonigral neurons from QUIN-induced excitotoxicity, suggesting that GDNF may be used for the treatment of striatonigral degenerative disorders, e.g. Huntington's disease and multiple system atrophy.
Pérez-Navarro
E
E
Departament de Biologia Cellular i Anatomia Patològica, Facultat de Medicina, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Universitat de Barcelona, Spain.
Arenas
E
E
Marco
S
S
Alberch
J
J
D000818:Animals; D016380:Brain Tissue Transplantation; D016923:Cell Death / Q000502:physiology; D002470:Cell Survival / Q000502:physiology; D003342:Corpus Striatum / Q000737:chemistry / Q000166:cytology / Q000637:transplantation*; D029721:Drosophila Proteins; D004745:Enkephalins / Q000032:analysis / Q000235:genetics; D005456:Fluorescent Dyes; D015971:Gene Expression Regulation, Enzymologic; D051100:Glial Cell Line-Derived Neurotrophic Factor; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D005968:Glutamate Decarboxylase / Q000032:analysis / Q000235:genetics; D006085:Graft Survival / Q000502:physiology; D017403:In Situ Hybridization; D008297:Male; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009474:Neurons / Q000737:chemistry / Q000166:cytology / Q000201:enzymology; D018696:Neuroprotective Agents / Q000378:metabolism*; D009498:Neurotoxins; D011498:Protein Precursors / Q000032:analysis / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics; D051096:Proto-Oncogene Proteins c-ret; D017378:Quinolinic Acid; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D011916:Rats, Inbred F344; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics; D011994:Recombinant Proteins / Q000235:genetics; D013266:Stilbamidines; D013378:Substantia Nigra / Q000737:chemistry / Q000166:cytology* / Q000502:physiology; D015320:Tachykinins / Q000032:analysis / Q000235:genetics