Pascual Alberto, Hidalgo-Figueroa María, Piruat José I, Pintado C Oscar, Gómez-Díaz Raquel, López-Barneo José
Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocío, Consejo Superior de Investigaciones Científicas, Universidad de Sevilla, Avenida Manuel Siurot s/n, 41013 Sevilla, Spain.
Nat Neurosci. 2008 Jul;11(7):755-61. doi: 10.1038/nn.2136. Epub 2008 Jun 8.
GDNF is a potent neurotrophic factor that protects catecholaminergic neurons from toxic damage and induces fiber outgrowth. However, the actual role of endogenous GDNF in the normal adult brain is unknown, even though GDNF-based therapies are considered promising for neurodegenerative disorders. We have generated a conditional GDNF-null mouse to suppress GDNF expression in adulthood, hence avoiding the developmental compensatory modifications masking its true physiologic action. After Gdnf ablation, mice showed a progressive hypokinesia and a selective decrease of brain tyrosine hydroxylase (Th) mRNA, accompanied by pronounced catecholaminergic cell death, affecting most notably the locus coeruleus, which practically disappears; the substantia nigra; and the ventral tegmental area. These data unequivocally demonstrate that GDNF is indispensable for adult catecholaminergic neuron survival and also show that, under physiologic conditions, downregulation of a single trophic factor can produce massive neuronal death.
胶质细胞源性神经营养因子（GDNF）是一种强效神经营养因子，可保护儿茶酚胺能神经元免受毒性损伤并诱导纤维生长。然而，内源性GDNF在正常成年大脑中的实际作用尚不清楚，尽管基于GDNF的疗法被认为对神经退行性疾病具有前景。我们构建了一种条件性GDNF基因敲除小鼠，以在成年期抑制GDNF表达，从而避免发育性代偿性改变掩盖其真正的生理作用。在敲除Gdnf后，小鼠表现出进行性运动功能减退以及脑酪氨酸羟化酶（Th）mRNA选择性降低，同时伴有明显的儿茶酚胺能细胞死亡，最显著影响蓝斑，蓝斑几乎消失；黑质；以及腹侧被盖区。这些数据明确表明，GDNF对成年儿茶酚胺能神经元的存活不可或缺，并且还表明，在生理条件下，单一营养因子的下调可导致大量神经元死亡。
