AAV-mediated gene delivery of BDNF or GDNF is neuroprotective in a model of Huntington disease.
Huntington disease (HD) is a neurodegenerative disorder that results in the progressive loss of GABAergic medium spiny projection neurons in the striatum. Neurotrophic factors have demonstrated neuroprotective actions on striatal neurons, suggesting that increased neurotrophic factor expression may prevent or reduce neuronal loss in the HD brain. We investigated whether enhanced expression of brain-derived neurotrophic factor (BDNF) or glial cell line-derived neurotrophic factor (GDNF), achieved by adeno-associated viral (AAV) vector-mediated gene delivery, could protect striatal neurons in the quinolinic acid (QA) rodent model of HD. Adult Wistar rats received unilateral intrastriatal injections of AAV-BDNF, AAV-GDNF, AAV-GFP, or PBS. Three weeks later, the rats were lesioned with QA, a toxin that induces striatal neuron death by an excitotoxic process. Both AAV-BDNF and AAV-GDNF significantly reduced the loss of both NeuN- and calbindin-immunopositive striatal neurons 2 weeks after lesion compared to controls. AAV-BDNF also provided significant neurotrophic support to NOS-immunopositive striatal interneurons, while AAV-GDNF-treated rats demonstrated significant protection of parvalbumin-immunopositive striatal interneurons compared to controls. These results indicate that AAV-mediated gene transfer of BDNF or GDNF into the striatum provides neuronal protection in a rodent model of HD.
Kells
Adrian P
AP
Department of Pharmacology and Clinical Pharmacology, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.
Fong
Dahna M
DM
Dragunow
Mike
M
During
Matthew J
MJ
Young
Deborah
D
Connor
Bronwen
B
D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics* / Q000378:metabolism; D064026:Calbindins; D002795:Choline O-Acetyltransferase / Q000032:analysis / Q000378:metabolism; D003342:Corpus Striatum / Q000473:pathology; D000229:Dependovirus / Q000235:genetics*; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics; D051100:Glial Cell Line-Derived Neurotrophic Factor; D006816:Huntington Disease / Q000139:chemically induced / Q000378:metabolism / Q000628:therapy*; D008297:Male; D009414:Nerve Growth Factors / Q000235:genetics*; D009474:Neurons / Q000473:pathology; D018696:Neuroprotective Agents; D019001:Nitric Oxide Synthase / Q000032:analysis / Q000378:metabolism; D010320:Parvalbumins / Q000032:analysis / Q000378:metabolism; D017378:Quinolinic Acid / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D064030:S100 Calcium Binding Protein G / Q000032:analysis / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D019208:Brain-Derived Neurotrophic Factor; D064026:Calbindins; C495041:Gdnf protein, rat; D051100:Glial Cell Line-Derived Neurotrophic Factor; D009414:Nerve Growth Factors; D018696:Neuroprotective Agents; D010320:Parvalbumins; D064030:S100 Calcium Binding Protein G; D005680:gamma-Aminobutyric Acid; D019001:Nitric Oxide Synthase; D002795:Choline O-Acetyltransferase; D017378:Quinolinic Acid