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  • Review Article
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Emerging roles of Wnts in the adult nervous system

Key Points

  • The expression of Wnt ligands and Wnt signalling components in the mature mammalian CNS suggests that this pathway might have a role in synaptic maintenance and function in adulthood.

  • At the presynaptic sites of central synapses, Wnt ligands modulate the synaptic vesicle cycle. Electrophysiological studies carried out in hippocampal slices of adult rodents are shedding light on the biological significance of Wnts in synaptic transmission.

  • At the postsynaptic sites of central synapses, non-canonical Wnt signalling induces rapid changes in the clustering of postsynaptic density protein 95 (PSD95) as well as NMDA (N-methyl-D-aspartate) and AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors. Calcium/calmodulin-dependent protein kinase II and Jun N-terminal kinase mediate these effects.

  • Wnt ligands are active in various types of stem cells (including astrocyte-like cells and neural stem cells), and they enhance hippocampal neurogenesis in vivo and Müller glia differentiation in retinal photoreceptors after injury. These findings could have important therapeutic implications.

  • Wnts regulate multiple aspects of midbrain dopaminergic neuron development, including patterning, morphogenesis, specification, proliferation, neurogenesis, precursor differentiation, survival and neuritogenesis. In addition, loss of function of the E3 ubiquitin ligase parkin leads to the accumulation of β-catenin, resulting in increased Wnt–β-catenin signalling, cell cycle re-entry and the death of postmitotic dopaminergic neurons, further suggesting a potential role for Wnt signalling in the pathogenesis of Parkinson's disease.

  • Loss of function of the Wnt pathway is as a relevant factor in Alzheimer's disease. This loss leads to an increase in amyloid-β formation and tau phosphorylation, which triggers synapse and neuron loss. WNT5A at the postsynaptic site regulates the synaptic localization of PSD95 and glutamate receptors and prevents the synaptotoxic effects of amyloid-β oligomers.

  • The fact that Wnt signalling is involved in several neurological diseases opens the possibility of therapeutic intervention through the modulation of different Wnt signalling components.

Abstract

The roles of the Wnt signalling pathway in several developmental processes, including synaptic differentiation, are well characterized. The expression of Wnt ligands and Wnt signalling components in the mature mammalian CNS suggests that this pathway might also play a part in synaptic maintenance and function. In fact, Wnts have a crucial role in synaptic physiology, as they modulate the synaptic vesicle cycle, the trafficking of neurotransmitter receptors and the interaction of these receptors with scaffold proteins in postsynaptic regions. In addition, Wnts participate in adult neurogenesis and protect excitatory synaptic terminals from amyloid-β oligomer toxicity. Here, the latest insights into the function of Wnt signalling in the adult nervous system and therapeutic opportunities for neurodegenerative diseases such as Alzheimer's and Parkinson's disease are discussed.

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Figure 1: The Wnt signalling pathways.
Figure 2: Canonical Wnt signalling regulates the presynaptic component of mature central synapses.
Figure 3: Non-canonical Wnt signalling regulates the postsynaptic component of mature central synapses.
Figure 4: Function of WNT1 and WNT5A in midbrain dopaminergic neuron development.
Figure 5: Hypothetical mechanism by which PD-related proteins may regulate Wnt signalling and the function of DA neurons.
Figure 6: Activation of Wnt signalling protects from amyloid toxicity.

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Acknowledgements

The authors wish to thank the members of their laboratories for comments on this Review. Work in N.C.I.'s laboratory is supported by grants from Comisión Nacional de Investigación Científica y Tecnológica (CONICYT) through a Base Centre for Excellence in Science and Technology, FONDAP (Fondo De Areas Prioritarias)-Biomedicine number 13980001 and the Millennium Institute for Fundamental and Applied Biology (MIFAB). Work in E.A.'s laboratory is supported by grants from the Swedish Foundation for Strategic Research (INGVAR (individual grant for the advancement of research leaders) and CEDB (Center of Excellence in Developmental Biology)), the Swedish Research Council (VR2008:2811, VR2008:3287 and DBRM (Developmental Biology for Regenerative Medicine)), the Norwegian Research Council, the Karolinska Institutet and the European Commission (Neurostemcell).

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Correspondence to Nibaldo C. Inestrosa.

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DATABASES

OMIM

Alzheimer's disease

Bardet–Biedl syndrome

Huntington's disease

Parkinson's disease

progressive myoclonus

epilepsy

FURTHER INFORMATION

Nibaldo C. Inestrosa's homepage

Ernest Arenas' homepage

Glossary

FM-1-43

An amphiphatic dye that becomes intensely fluorescent when inserted into the cell membrane. It is used in a wide variety of studies involving the plasma membrane and vesiculation.

Miniature excitatory postsynaptic current

(mEPSC). The postsynaptic current that is evoked by release of a single vesicle of neurotransmitter from the presynaptic terminal into the synapse.

Active zone

The portion of the presynaptic membrane located opposite the postsynaptic density. It is the site of synaptic vesicle docking and neurotransmitter release.

Field EPSP

(fEPSP). The extracellular signal recorded from a population of neurons when they all receive synaptic inputs from afferent axonic fibres. It is possible to make field recordings only in those areas of the brain, such as the hippocampus, in which the neurons are arranged in such a way that they all receive synaptic inputs from the same afferent.

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Inestrosa, N., Arenas, E. Emerging roles of Wnts in the adult nervous system. Nat Rev Neurosci 11, 77–86 (2010). https://doi.org/10.1038/nrn2755

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