The regulation and deregulation of Wnt signaling by PARK genes in health and disease

Abstract

Wingless/Int (Wnt) signaling pathways are signal transduction mechanisms that have been widely studied in the field of embryogenesis. Recent work has established a critical role for these pathways in brain development, especially of midbrain dopaminergic neurones. However, the fundamental importance of Wnt signaling for the normal function of mature neurones in the adult central nervous system has also lately been demonstrated by an increasing number of studies. Parkinson's disease (PD) is the second most prevalent neurodegenerative disease worldwide and is currently incurable. This debilitating disease is characterized by the progressive loss of a subset of midbrain dopaminergic neurones in the substantia nigra leading to typical extrapyramidal motor symptoms. The aetiology of PD is poorly understood but work performed over the last two decades has identified a growing number of genetic defects that underlie this condition. Here we review a growing body of data connecting genes implicated in PD--most notably the PARK genes--with Wnt signaling. These observations provide clues to the normal function of these proteins in healthy neurones and suggest that deregulated Wnt signaling might be a frequent pathomechanism leading to PD. These observations have implications for the pathogenesis and treatment of neurodegenerative diseases in general.

Keywords: LRRK2; Parkinson's disease; Wnt signaling; genetics of Parkinson's disease; neurodegeneration; treatment.

Figure 1

Potential sites of canonical Wnt signaling deregulation in PD. As outlined in the main text, six proteins—GSK3β, LRRK2, Nurr1, Parkin, VPS35, and WNT3—have been linked to canonical Wnt signaling and genetic risk of PD. The sites where these proteins affect the canonical pathway are represented graphically. The diagram is divided into three sections; from left-to-right these are (i) basal canonical Wnt signaling, (ii) activated Wnt signaling, and (iii) Wnt secretion. (i) In the basal state, β-catenin, the main effector of the canonical Wnt pathway, is repressed by GSK3β, LRRK2, and Parkin. GSK3β phosphorylates β-catenin, triggering the ubiquitination (Ub) of this protein by Parkin, leading to the proteosomal degradation of β-catenin. (ii) Upon binding of Wnt ligand such as WNT3, LRRK2, β-catenin, GSK3β, and associated proteins are recruited to membrane receptor complexes. The phosphorylation of β-catenin by GSK3β is repressed, stabilizing β-catenin and allowing this protein to enter the nucleus. Nuclear β-catenin binds and transactivates target transcription factors including Nurr1, driving the expression of downstream genes. In both basal and activated conditions LRRK2 functions as a scaffolding protein. (iii) Wnt ligand secretion is mediated by Wntless (WTL), which transports Wnt ligands from the trans-Golgi network to the plasma membrane where Wnts are released. This process is dependent on the recycling of Wntless back from the plasma membrane, via early endosomes to the trans-Golgi network. This last step is mediated by the retromer complex, of which VPS35 is an essential component. Loss of VPS35 function leads to an accumulation of Wntless in the endosomal system, and decreased secretion of Wnt ligands.