FGF-2 promotes neurogenesis and neuroprotection and prolongs survival in a transgenic mouse model of Huntington's disease.
There is no satisfactory treatment for Huntington's disease (HD), a hereditary neurodegenerative disorder that produces chorea, dementia, and death. One potential treatment strategy involves the replacement of dead neurons by stimulating the proliferation of endogenous neuronal precursors (neurogenesis) and their migration into damaged regions of the brain. Because growth factors are neuroprotective in some settings and can also stimulate neurogenesis, we treated HD transgenic R6/2 mice from 8 weeks of age until death by s.c. administration of FGF-2. FGF-2 increased the number of proliferating cells in the subventricular zone by approximately 30% in wild-type mice, and by approximately 150% in HD transgenic R6/2 mice. FGF-2 also induced the recruitment of new neurons from the subventricular zone into the neostriatum and cerebral cortex of HD transgenic R6/2 mice. In the striatum, these neurons were DARPP-32-expressing medium spiny neurons, consistent with the phenotype of neurons lost in HD. FGF-2 was neuroprotective as well, because it blocked cell death induced by mutant expanded Htt in primary striatal cultures. FGF-2 also reduced polyglutamine aggregates, improved motor performance, and extended lifespan by approximately 20%. We conclude that FGF-2 improves neurological deficits and longevity in a transgenic mouse model of HD, and that its neuroprotective and neuroproliferative effects may contribute to this improvement.
Jin
Kunlin
K
The Buck Institute for Age Research, Novato, CA 94945, USA.
LaFevre-Bernt
Michelle
M
Sun
Yunjuan
Y
Chen
Sylvia
S
Gafni
Juliette
J
Crippen
Danielle
D
Logvinova
Anna
A
Ross
Christopher A
CA
Greenberg
David A
DA
Ellerby
Lisa M
LM
D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D001973:Bromodeoxyuridine; D016923:Cell Death / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects*; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32 / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D006816:Huntington Disease / Q000378:metabolism / Q000628:therapy*; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic; D039902:Multipotent Stem Cells / Q000166:cytology* / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000378:metabolism*
D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; C497929:Ppp1r1b protein, mouse; D016222:Fibroblast Growth Factor 2; D001973:Bromodeoxyuridine