Glial cell line-derived neurotrophic factor partially ameliorates motor symptoms without slowing neurodegeneration in mice with respiratory chain-deficient dopamine neurons.
Degeneration of midbrain dopamine neurons causes the striatal dopamine deficiency responsible for the hallmark motor symptoms of Parkinson's disease (PD). Intraparenchymal delivery of neurotrophic factors, such as glial cell line-derived neurotrophic factor (GDNF), is a possible future therapeutic approach. In animal PD models, GDNF can both ameliorate neurodegeneration and promote recovery of the dopamine system following a toxic insult. However, clinical studies have generated mixed results, and GDNF has not been efficacious in genetic animal models based on α-synuclein overexpression. We have tested the response to GDNF in a genetic mouse PD model with progressive degeneration of dopamine neurons caused by mitochondrial impairment. We find that GDNF, delivered to the striatum by either an adeno-associated virus or via miniosmotic pumps, partially alleviates the progressive motor symptoms without modifying the rate of neurodegeneration. These behavioral changes are accompanied by increased levels of dopamine in the midbrain, but not in striatum. At high levels, GDNF may instead reduce striatal dopamine levels. These results demonstrate the therapeutic potential of GDNF in a progressively impaired dopamine system.
Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
Fredrik H
FH
Sterky
Karin
K
Pernold
Brandon K
BK
Harvey
Eva
E
Lindqvist
Barry J
BJ
Hoffer
Lars
L
Olson
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000378:metabolism / Q000473:pathology; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics; D051098:Glial Cell Line-Derived Neurotrophic Factors / Q000008:administration & dosage* / Q000235:genetics*; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D011897:Random Allocation
D050483:Dopamine Plasma Membrane Transport Proteins; D051098:Glial Cell Line-Derived Neurotrophic Factors; D004298:Dopamine