von Bohlen und Halbach Oliver, Minichiello Liliana, Unsicker Klaus
Interdisciplinary Center for Neurosciences (IZN), Department of Neuroanatomy, University of Heidelberg, Heidelberg, Germany.
FASEB J. 2005 Oct;19(12):1740-2. doi: 10.1096/fj.05-3845fje. Epub 2005 Jul 21.
The neurotrophins brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) have been shown to promote survival and differentiation of midbrain dopaminergic (DAergic) neurons in vitro and in vivo. This is consistent with their expression and that of their cognate receptors, trkB and trkC, in the nigrostriatal system. Degeneration of DAergic neurons of the substantia nigra and alpha-synuclein-positive aggregates in the remaining substantia nigra (SN) neurons are hallmarks of Parkinson's disease (PD). Reduced expression of BDNF has been reported in the SN from PD patients. Moreover, mutations in the BDNF gene have been found to play a role in the development of familial PD. We show now that haploinsufficiencies of the neurotrophin receptors trkB and/or trkC cause a reduction in numbers of SN neurons in aged (21-23 month old) mice, which is accompanied by a reduced density in striatal tyrosine hydroxylase immunoreactive (TH-ir) fibers. These aged mutant mice, in contrast to wild-type littermates, display an accumulation of alpha-synuclein in the remaining TH-positive neurons of the SN. We conclude that impairment in trkB and/or trkC signaling induces a phenotype in the aged SN, which includes two hallmarks of PD, losses of TH positive neurons and axons along with massive neuronal deposits of alpha-synuclein.
神经营养因子脑源性神经营养因子（BDNF）和神经营养因子-3（NT-3）已被证明在体外和体内均可促进中脑多巴胺能（DAergic）神经元的存活和分化。这与其在黑质纹状体系统中的表达及其同源受体trkB和trkC的表达一致。黑质多巴胺能神经元的变性以及剩余黑质（SN）神经元中α-突触核蛋白阳性聚集体是帕金森病（PD）的标志。据报道，PD患者黑质中BDNF的表达降低。此外，已发现BDNF基因的突变在家族性PD的发展中起作用。我们现在表明，神经营养因子受体trkB和/或trkC的单倍剂量不足会导致老年（21-23月龄）小鼠SN神经元数量减少，同时伴有纹状体酪氨酸羟化酶免疫反应性（TH-ir）纤维密度降低。与野生型同窝小鼠相比，这些老年突变小鼠在SN剩余的TH阳性神经元中显示出α-突触核蛋白的积累。我们得出结论，trkB和/或trkC信号传导受损会在老年SN中诱导一种表型，其中包括PD的两个标志，即TH阳性神经元和轴突的丧失以及α-突触核蛋白的大量神经元沉积。
