TY - JOUR
T1 - Viral delivery of glial cell line-derived neurotrophic factor improves behavior and protects striatal neurons in a mouse model of Huntington's disease
AU - McBride, Jodi L.
AU - Ramaswamy, Shilpa
AU - Gasmi, Mehdi
AU - Bartus, Raymond T.
AU - Herzog, Christopher D.
AU - Brandon, Eugene P.
AU - Zhou, Lili
AU - Pitzer, Mark R.
AU - Berry-Kravis, Elizabeth M.
AU - Kordower, Jeffrey H.
PY - 2006/6/13
Y1 - 2006/6/13
N2 - Huntington's disease (HD) is a fatal, genetic, neurological disorder resulting from a trinucleotide repeat expansion in the gene that encodes for the protein huntingtin. These excessive repeats confer a toxic gain of function on huntingtin, which leads to the degeneration of striatal and cortical neurons and a devastating motor, cognitive, and psychological disorder. Trophic factor administration has emerged as a compelling potential therapy for a variety of neurodegenerative disorders, including HD. We previously demonstrated that viral delivery of glial cell line-derived neurotrophic factor (GDNF) provides structural and functional neuroprotection in a rat neurotoxin model of HD. In this report we demonstrate that viral delivery of GDNF into the striatum of presymptomatic mice ameliorates behavioral deficits on the accelerating rotorod and hind limb clasping tests in transgenic HD mice. Behavioral neuroprotection was associated with anatomical preservation of the number and size of striatal neurons from cell death and cell atrophy. Additionally, GDNF-treated mice had a lower percentage of neurons containing mutant huntingtin-stained inclusion bodies, a hallmark of HD pathology. These data further support the concept that viral vector delivery of GDNF may be a viable treatment for patients suffering from HD.
AB - Huntington's disease (HD) is a fatal, genetic, neurological disorder resulting from a trinucleotide repeat expansion in the gene that encodes for the protein huntingtin. These excessive repeats confer a toxic gain of function on huntingtin, which leads to the degeneration of striatal and cortical neurons and a devastating motor, cognitive, and psychological disorder. Trophic factor administration has emerged as a compelling potential therapy for a variety of neurodegenerative disorders, including HD. We previously demonstrated that viral delivery of glial cell line-derived neurotrophic factor (GDNF) provides structural and functional neuroprotection in a rat neurotoxin model of HD. In this report we demonstrate that viral delivery of GDNF into the striatum of presymptomatic mice ameliorates behavioral deficits on the accelerating rotorod and hind limb clasping tests in transgenic HD mice. Behavioral neuroprotection was associated with anatomical preservation of the number and size of striatal neurons from cell death and cell atrophy. Additionally, GDNF-treated mice had a lower percentage of neurons containing mutant huntingtin-stained inclusion bodies, a hallmark of HD pathology. These data further support the concept that viral vector delivery of GDNF may be a viable treatment for patients suffering from HD.
KW - Adenoassociated virus
KW - Gene therapy
KW - Neurodegeneration
KW - Neuroprotection
KW - Polyglutamine
UR - http://www.scopus.com/inward/record.url?scp=33745178085&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33745178085&partnerID=8YFLogxK
U2 - 10.1073/pnas.0508875103
DO - 10.1073/pnas.0508875103
M3 - Article
C2 - 16751280
AN - SCOPUS:33745178085
SN - 0027-8424
VL - 103
SP - 9345
EP - 9350
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 24
ER -