Ex vivo delivery of GDNF maintains motor function and prevents neuronal loss in a transgenic mouse model of Huntington's disease.
Huntington's disease (HD) is an autosomal dominant disorder caused by expansion of polyglutamine repeats in the huntingtin gene leading to loss of striatal and cortical neurons followed by deficits in cognition and choreic movements. Growth factor delivery to the brain has shown promise in various models of neurodegenerative diseases, including HD, by reducing neuronal death and thus limiting motor impairment. Here we used mouse neural progenitor cells (mNPCs) as growth factor delivery vehicles in the N171-82Q transgenic mouse model of HD. mNPCs derived from the developing mouse striatum were isolated and infected with lentivirus expressing either glial cell line-derived neurotrophic factor (GDNF) or green fluorescent protein (GFP). Next, mNPCs(GDNF) or mNPCs(GFP) were transplanted bilaterally into the striatum of pre-symptomatic N171-82Q mice. We found that mNPCs(GDNF), but not mNPCs(GFP), maintained rotarod function and increased striatal neuron survival out to 3months post-transplantation. Importantly, histological analysis showed GDNF expression through the duration of the experiment. Our data show that mNPCs(GDNF) can survive transplantation, secrete GDNF for several weeks and are able to maintain motor function in this model of HD.
Stem Cell and Regenerative Medicine Center, University of Wisconsin-Madison, 1111 Highland Ave., Madison, WI 53705, USA. aebert@wisc.edu
Allison D
AD
Ebert
Amelia E
AE
Barber
Brittany M
BM
Heins
Clive N
CN
Svendsen
D000704:Analysis of Variance; D000818:Animals; D001835:Body Weight; D002452:Cell Count; D002478:Cells, Cultured; D003342:Corpus Striatum / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D015316:Genetic Therapy; D005822:Genetic Vectors; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000008:administration & dosage* / Q000235:genetics; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D007150:Immunohistochemistry; D016086:Lentivirus / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D009043:Motor Activity / Q000235:genetics; D009410:Nerve Degeneration / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D045442:Rotarod Performance Test; D033581:Stem Cell Transplantation
D051100:Glial Cell Line-Derived Neurotrophic Factor; D004298:Dopamine