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Background  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.    Results   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 [ 3 H] 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.    Conclusion  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.

molecular neurodegeneration

A Wnt1 regulated Frizzled-1/β-Cateninsignaling pathway as a candidate regulatory circuit controlling mesencephalic dopaminergic neuron-astrocyte crosstalk: Therapeutical relevance for neuron survival and neuroprotection