A Wnt1 regulated Frizzled-1/β-Catenin signaling pathway as a candidate regulatory circuit controlling mesencephalic dopaminergic neuron-astrocyte crosstalk: Therapeutical relevance for neuron survival and neuroprotection.
A Wnt1 regulated Frizzled-1/β-Catenin signaling pathway as a candidate regulatory circuit controlling mesencephalic dopaminergic neuron-astrocyte crosstalk: Therapeutical relevance for neuron survival and neuroprotection.
复制标题
DOI：
10.1186/1750-1326-6-49
复制
发表时间：
2011-07-13
影响因子：
15.1
通讯作者：
Marchetti B
中科院分区：
文献类型：
--
作者：
L'episcopo F;Serapide MF;Tirolo C;Testa N;Caniglia S;Morale MC;Pluchino S;Marchetti B
中脑腹侧的多巴胺能神经元是控制运动行为、认知和情感功能的关键神经元，其产生依赖于其祖细胞中无翅型MMTV整合位点（Wnt）/β-catenin通路的激活。在帕金森氏病中，黑质内的DA细胞体（SNpc）进行性退化，原因和机制知之甚少。新出现的证据表明，通过卷曲（Fzd）受体的Wnt信号可能在不同的退行性疾病中发挥作用，但对成年中脑中的Wnt信号知之甚少。使用体外和体内DA变性模型系统，沿着在完整和SN损伤小鼠中的功能研究，我们在此强调内在Wnt 1/Fzd-1/β-catenin张力对成年中脑DA神经元的存活和保护至关重要。体外实验在表达多巴胺转运蛋白（DAT）的神经元中在mRNA和蛋白质水平上鉴定了Fzd-1受体表达，并证明了外源性Wnt 1能够对由不同DA特异性损伤（包括血清和生长因子剥夺）诱导的Caspase-3活化、酪氨酸羟化酶阳性（TH+）神经元损失和[3 H]多巴胺摄取发挥强大的神经保护作用，6-羟基多巴胺和MPTP/MPP+。DA神经元与中脑星形胶质细胞的共培养表型复制Wnt 1的神经保护作用，而RNA干扰介导的敲低中脑星形胶质细胞中的Wnt 1显著降低星形胶质细胞诱导的TH+神经保护作用。同样地，在中脑神经元中沉默β-catenin mRNA或敲低Fzd-1受体表达抵消星形胶质细胞诱导的TH+神经保护。体内实验证明Fzd-1与完整SNpc内的TH+神经元共定位，并且通过在SN内单侧输注Fzd/β-连环蛋白拮抗剂来阻断Fzd/β-连环蛋白信号传导诱导反应性星形胶质细胞增多并急性抑制同侧SNpc中的TH+神经元存活，这是通过SNpc内的β-连环蛋白信号传导的药理学激活有效防止的作用。这些结果定义了一种新的Wnt 1/Fzd-1/β-catenin星形胶质细胞-DA自保护环，为促生存过程的调节提供了一种新的机制，对帕金森病的药物设计或药物作用具有潜在的相关影响。
Dopamine-synthesizing (dopaminergic, DA) neurons in the ventral midbrain (VM) constitute a pivotal neuronal population controlling motor behaviors, cognitive and affective brain functions, which generation critically relies on the activation of Wingless-type MMTV integration site (Wnt)/β-catenin pathway in their progenitors. In Parkinson's disease, DA cell bodies within the substantia nigra pars compacta (SNpc) progressively degenerate, with causes and mechanisms poorly understood. Emerging evidence suggests that Wnt signaling via Frizzled (Fzd) receptors may play a role in different degenerative states, but little is known about Wnt signaling in the adult midbrain. Using in vitro and in vivo model systems of DA degeneration, along with functional studies in both intact and SN lesioned mice, we herein highlight an intrinsic Wnt1/Fzd-1/β-catenin tone critically contributing to the survival and protection of adult midbrain DA neurons. In vitro experiments identifie Fzd-1 receptor expression at a mRNA and protein levels in dopamine transporter (DAT) expressing neurons, and demonstrate the ability of exogenous Wnt1 to exert robust neuroprotective effects against Caspase-3 activation, the loss of tyrosine hydroxylase-positive (TH+) neurons and [3H] dopamine uptake induced by different DA-specific insults, including serum and growth factor deprivation, 6-hydroxydopamine and MPTP/MPP+. Co-culture of DA neurons with midbrain astrocytes phenocopies Wnt1 neuroprotective effects, whereas RNA interference-mediated knockdown of Wnt1 in midbrain astrocytes markedly reduces astrocyte-induced TH+ neuroprotection. Likewise, silencing β-catenin mRNA or knocking down Fzd-1 receptor expression in mesencephalic neurons counteract astrocyte-induced TH+ neuroprotection. In vivo experiments document Fzd-1 co-localization with TH+ neurons within the intact SNpc and blockade of Fzd/β-catenin signaling by unilateral infusion of a Fzd/β-catenin antagonist within the SN induces reactive astrocytosis and acutely inhibits TH+ neuron survival in ipsilateral SNpc, an effect efficiently prevented by pharmacological activation of β-catenin signaling within the SNpc. These results defining a novel Wnt1/Fzd-1/β-catenin astrocyte-DA autoprotective loop provide a new mechanistic inside into the regulation of pro-survival processes, with potentially relevant consequences for drug design or drug action in Parkinson's disease.