Neurturin protects striatal projection neurons but not interneurons in a rat model of Huntington's disease.
Glial cell line-derived neurotrophic factor and neurturin are neurotrophic factors expressed in the striatum during development and in the adult rat. Both molecules act as target-derived neurotrophic factors for nigrostriatal dopaminergic neurons. While glial cell line-derived neurotrophic factor has also been described to have local trophic effects on striatal neurons, the effects of neurturin in the striatum have not yet been described. Here we examine whether neurturin protects striatal projection neurons (calbindin-positive) and interneurons (parvalbumin- or choline acetyltransferase-positive) in an animal model of Huntington's disease. A fibroblast cell line engineered to over-express neurturin was grafted into adult rat striatum 24h before quinolinate injection. In animals grafted with a control cell line, intrastriatal quinolinate injection reduced the number of calbindin-, parvalbumin- and choline acetyltransferase-positive neurons, seven days post-lesion. Intrastriatal grafting of neurturin-secreting cells protected striatal projection neurons, but not interneurons, from quinolinate excitotoxicity. This effect was much more robust than that reported previously for a glial cell line-derived neurotrophic factor-secreting cell line on striatal calbindin-positive neurons. However, intrastriatal grafting of glial cell line-derived neurotrophic factor- but not neurturin-secreting cells prevented the decrease in choline acetyltransferase activity induced by quinolinate injection. Taken together, our results show that neurturin- and glial cell line-derived neurotrophic factor-secreting cell lines have clearly differential effects on striatal neurons. Grafting of the neurturin-secreting cell line showed a more specific and efficient trophic effect on striatal projection neurons, the neuronal population most affected in Huntington's disease. Therefore, our results suggest that neurturin is a good candidate for the treatment of this neurodegenerative disorder.
Pérez-Navarro
E
E
Departament de Biologia Cellular i Anatomia Patològica, Facultat de Medicina, IDIBAPS, Universitat de Barcelona, Casanova 143, E-08036, Barcelona, Spain.
Akerud
P
P
Marco
S
S
Canals
J M
JM
Tolosa
E
E
Arenas
E
E
Alberch
J
J
D000818:Animals; D064026:Calbindins; D002452:Cell Count; D002795:Choline O-Acetyltransferase / Q000032:analysis / Q000378:metabolism; D003342:Corpus Striatum / Q000166:cytology*; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects; D005347:Fibroblasts / Q000502:physiology / Q000637:transplantation; D015870:Gene Expression / Q000502:physiology; D051100:Glial Cell Line-Derived Neurotrophic Factor; D006816:Huntington Disease / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D007395:Interneurons / Q000737:chemistry / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D009410:Nerve Degeneration / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology; D009414:Nerve Growth Factors / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics; D009434:Neural Pathways; D018696:Neuroprotective Agents / Q000378:metabolism*; D009498:Neurotoxins; D051101:Neurturin; D010320:Parvalbumins / Q000032:analysis; D017378:Quinolinic Acid; D051381:Rats; D011916:Rats, Inbred F344; D064030:S100 Calcium Binding Protein G / Q000032:analysis; D014162:Transfection
D064026:Calbindins; C495041:Gdnf protein, rat; D051100:Glial Cell Line-Derived Neurotrophic Factor; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D009498:Neurotoxins; D051101:Neurturin; C495057:Nrtn protein, rat; D010320:Parvalbumins; D064030:S100 Calcium Binding Protein G; D002795:Choline O-Acetyltransferase; D017378:Quinolinic Acid