Wnt Signaling as a Potential Therapeutic Target for Frontotemporal Dementia

Department of Psychiatry and Vanderbilt Kennedy Center for Research on Human Development, Vanderbilt University, Nashville, TN 37232, USA.
Neuron (Impact Factor: 15.05). 09/2011; 71(6):955-7. DOI: 10.1016/j.neuron.2011.09.002
Source: PubMed


Figure 1. Reduced expression levels of Progranulin (GRN) are present from early embryonic life. However, the clinical symptoms of disease arise more than half a century later. Initially, the disease is in its latent, compensated phase. During this time the pathophysiological events slowly progress, but compensatory mechanisms presumably prevent the emergence of the disease phenotype. In this latent disease phase, progranulin deficiency triggers a complex dysregulation of the Wnt signaling pathway, where gene products belonging to the stimulatory, canonical Wnt pathway are upregulated, while negative regulators of Wnt signaling show reduced expression levels. This results in disruption of mitochondrial energy metabolism, inefficient protein degradation and altered cell cycling. At this phase, Wnt dysregulation might be, at least partially, a compensatory event, which is likely to become detrimental over a prolonged period of time. The neurodegenerative phase is characterized by lysosomal alterations, appearance of complex inflammatory processes, disrupted synaptic transmission, myelination defects, and appearance of TDP-43 inclusions, which jointly lead to neuronal death. During this neurodegenerative phase Wnt signaling changes are likely to be detrimental to brain function, rather than compensatory. The molecular pathology and cell loss ultimately result in functional disturbances and clinical diagnosis of FTD.

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