title: 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.
authors.affiliation: Department of Pharmacology, UCL School of Pharmacy, University College London, 29-39 Brunswick Square, London WC1N 1AX, UK.
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Berwick
authors.forename: Kirsten
authors.initials: K
authors.lastname: Harvey
mesh_terms: D001921:Brain / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D008954:Models, Biological; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000378:metabolism; D010300:Parkinson Disease / Q000235:genetics* / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D060449:Wnt Signaling Pathway / Q000502:physiology*
chemical_list: D044767:Ubiquitin-Protein Ligases; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases
keywords: LRRK2; Parkinson's disease; Wnt signaling; genetics of Parkinson's disease; neurodegeneration; treatment