| Summary: | <p>Abstract</p> <p>Background</p> <p>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 <it>Wingless-type MMTV integration site (Wnt)/β-catenin </it>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 <it>Wnt </it>signaling via <it>Frizzled </it>(<it>Fzd</it>) receptors may play a role in different degenerative states, but little is known about <it>Wnt </it>signaling in the adult midbrain. Using <it>in vitro </it>and <it>in vivo </it>model systems of DA degeneration, along with functional studies in both intact and SN lesioned mice, we herein highlight an intrinsic <it>Wnt1/Fzd-1/β-catenin </it>tone critically contributing to the survival and protection of adult midbrain DA neurons.</p> <p>Results</p> <p><it>In vitro </it>experiments identifie <it>Fzd-1 </it>receptor expression at a mRNA and protein levels in dopamine transporter (DAT) expressing neurons, and demonstrate the ability of exogenous <it>Wnt1 </it>to exert robust neuroprotective effects against Caspase-3 activation, the loss of tyrosine hydroxylase-positive (TH<sup>+</sup>) neurons and [<sup>3</sup>H] dopamine uptake induced by different DA-specific insults, including serum and growth factor deprivation, 6-hydroxydopamine and MPTP/MPP<sup>+</sup>. Co-culture of DA neurons with midbrain astrocytes phenocopies <it>Wnt1 </it>neuroprotective effects, whereas RNA interference-mediated knockdown of <it>Wnt1 </it>in midbrain astrocytes markedly reduces astrocyte-induced TH<sup>+ </sup>neuroprotection. Likewise, silencing <it>β-catenin </it>mRNA or knocking down <it>Fzd-1 receptor expression </it>in mesencephalic neurons counteract astrocyte-induced TH<sup>+ </sup>neuroprotection. <it>In vivo </it>experiments document <it>Fzd-1 </it>co-localization with TH<sup>+ </sup>neurons within the intact SNpc and blockade of <it>Fzd/β-catenin </it>signaling by unilateral infusion of a <it>Fzd/β-catenin </it>antagonist within the SN induces reactive astrocytosis and acutely inhibits TH<sup>+ </sup>neuron survival in ipsilateral SNpc, an effect efficiently prevented by pharmacological activation of <it>β-catenin </it>signaling within the SNpc.</p> <p>Conclusion</p> <p>These results defining a novel <it>Wnt1/Fzd-1/β-catenin </it>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.</p>
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