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The genetics of Parkinson's disease: progress and therapeutic implications.

Abstract

The past 15 years has witnessed tremendous progress in our understanding of the genetic basis for Parkinson's disease (PD). Notably, whereas most mutations, such as those in SNCA, PINK1, PARK2, PARK7, PLA2G6, FBXO7, and ATP13A2, are a rare cause of disease, one particular mutation in LRRK2 has been found to be common in certain populations. There has been considerable progress in finding risk loci. To date, approximately 16 such loci exist; notably, some of these overlap with the genes known to contain disease-causing mutations. The identification of risk alleles has relied mostly on the application of revolutionary technologies; likewise, second-generation sequencing methods have facilitated the identification of new mutations in PD. These methods will continue to provide novel insights into PD. The utility of genetics in therapeutics relies primarily on leveraging findings to understand the pathogenesis of PD. Much of the investigation into the biology underlying PD has used these findings to define a pathway, or pathways, to pathogenesis by trying to fit disparate genetic defects onto the same network. This work has had some success, particularly in the context of monogenic disease, and is beginning to provide clues about potential therapeutic targets. Approaches toward therapies are also being provided more directly by genetics, notably by the reduction and clearance of alpha-synuclein and inhibition of Lrrk2 kinase activity. We believe this has been an exciting, productive time for PD genetics and, furthermore, that genetics will continue to drive the etiologic understanding and etiology-based therapeutic approaches in this disease.

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  • Authors+Show Affiliations

    ,

    Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland 20892, USA. singleta@mail.nih.gov

    ,

    Source

    MeSH

    Disease Progression
    Genetic Predisposition to Disease
    Humans
    Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
    Mutation
    Nerve Tissue Proteins
    Parkinson Disease
    Protein-Serine-Threonine Kinases
    alpha-Synuclein

    Pub Type(s)

    Journal Article
    Research Support, N.I.H., Extramural
    Research Support, N.I.H., Intramural
    Research Support, Non-U.S. Gov't
    Review

    Language

    eng

    PubMed ID

    23389780

    Citation

    TY - JOUR T1 - The genetics of Parkinson's disease: progress and therapeutic implications. AU - Singleton,Andrew B, AU - Farrer,Matthew J, AU - Bonifati,Vincenzo, PY - 2012/04/25/received PY - 2012/08/22/revised PY - 2012/09/20/accepted PY - 2013/2/8/entrez PY - 2013/2/8/pubmed PY - 2013/8/22/medline SP - 14 EP - 23 JF - Movement disorders : official journal of the Movement Disorder Society JO - Mov. Disord. VL - 28 IS - 1 N2 - The past 15 years has witnessed tremendous progress in our understanding of the genetic basis for Parkinson's disease (PD). Notably, whereas most mutations, such as those in SNCA, PINK1, PARK2, PARK7, PLA2G6, FBXO7, and ATP13A2, are a rare cause of disease, one particular mutation in LRRK2 has been found to be common in certain populations. There has been considerable progress in finding risk loci. To date, approximately 16 such loci exist; notably, some of these overlap with the genes known to contain disease-causing mutations. The identification of risk alleles has relied mostly on the application of revolutionary technologies; likewise, second-generation sequencing methods have facilitated the identification of new mutations in PD. These methods will continue to provide novel insights into PD. The utility of genetics in therapeutics relies primarily on leveraging findings to understand the pathogenesis of PD. Much of the investigation into the biology underlying PD has used these findings to define a pathway, or pathways, to pathogenesis by trying to fit disparate genetic defects onto the same network. This work has had some success, particularly in the context of monogenic disease, and is beginning to provide clues about potential therapeutic targets. Approaches toward therapies are also being provided more directly by genetics, notably by the reduction and clearance of alpha-synuclein and inhibition of Lrrk2 kinase activity. We believe this has been an exciting, productive time for PD genetics and, furthermore, that genetics will continue to drive the etiologic understanding and etiology-based therapeutic approaches in this disease. SN - 1531-8257 UR - https://www.unboundmedicine.com/medline/citation/23389780/full_citation L2 - http://dx.doi.org/10.1002/mds.25249 ER -