Genetic variability at the PARK16 locus

Department of Molecular Neuroscience and Reta Lila Weston Institute, UCL Institute of Neurology, London, UK.
European journal of human genetics: EJHG (Impact Factor: 4.23). 12/2010; 18(12):1356-9. DOI: 10.1038/ejhg.2010.125
Source: PubMed

ABSTRACT Parkinson's disease (PD) is a complex neurodegenerative disease which is clinically heterogeneous and pathologically consists of loss of dopaminergic neurons in the substantia nigra and intracytoplasmic neuronal inclusions containing alpha-synuclein aggregations known as Lewy bodies. Although the majority of PD is idiopathic, pathogenic mutations in several mendelian genes have been successfully identified through linkage analyses. To identify susceptibility loci for idiopathic PD, several genome-wide association studies (GWAS) within different populations have recently been conducted in both idiopathic and familial forms of PD. These analyses have confirmed SNCA and MAPT as loci harboring PD susceptibility. In addition, the GWAS identified several other genetic loci suggestively associated with the risk of PD; among these, only one was replicated by two different studies of European and Asian ancestries. Hence, we investigated this novel locus known as PARK16 for coding mutations in a large series of idiopathic pathologically proven PD cases, and also conducted an association study in a case-control cohort from the United Kingdom. An association between a novel RAB7L1 mutation, c.379-12insT, and disease (P-value=0.0325) was identified. Two novel coding variants present only in the PD cohort were also identified within the RAB7L1 (p.K157R) and SLC41A1 (p.A350V) genes. No copy number variation analyses have yet been performed within this recently identified locus. We concluded that, although both coding variants and risk alleles within the PARK16 locus seem to be rare, further molecular analyses within the PARK16 locus and within different populations are required in order to examine its biochemical role in the disease process.

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Available from: Coro Paisán-Ruiz, Aug 12, 2015
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    • "For example, Rab7L1 regulates the intraneuronal sorting of LRRK2 and also Rab7L1 gene is located in a locus harboring PD susceptibility [67] [68]. Reduced neurite extension in cultured neurons harboring mutant LRRK2 can be rescued by overexpression of Rab7L1 supporting the idea that proper sorting is critical to its function [67]. 14-3-3 proteins may act in a similar fashion to regulate intracellular LRRK2 protein localization. "
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    ABSTRACT: 14-3-3 proteins are abundantly expressed adaptor proteins that interact with a vast number of binding partners to regulate their cellular localization and function. They regulate substrate function in a number of ways including protection from dephosphorylation, regulation of enzyme activity, formation of ternary complexes and sequestration. The diversity of 14-3-3 interacting partners thus enables 14-3-3 proteins to impact a wide variety of cellular and physiological processes. 14-3-3 proteins are broadly expressed in the brain, and clinical and experimental studies have implicated 14-3-3 proteins in neurodegenerative disease. A recurring theme is that 14-3-3 proteins play important roles in pathogenesis through regulating the subcellular localization of target proteins. Here, we review the evidence that 14-3-3 proteins regulate aspects of neurodegenerative disease with a focus on their protective roles against neurodegeneration.
    12/2013; 2013:564534. DOI:10.1155/2013/564534
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    • "Although linkage analysis along with candidate gene screening was traditionally the preferred method for gene discovery in inherited MDs (Paisan-Ruiz et al., 2004, 2005), these are not appropriate for families with largely reduced penetrance or reduced number of affected individuals. And even though there has been considerable success in identifying genetic risk factors for PD and PSP through the application of genome-wide association studies (GWAS; Simon-Sanchez et al., 2009; Hamza et al., 2010; Hoglinger et al., 2011), a detailed mapping through targeted resequencing (TR) is still required to further identify both high-risk alleles and haplotypes (Tucci et al., 2010; Freedman et al., 2011). By contrast, next-generation sequencing (NGS) technologies, such as exome sequencing (ES) and whole-genome sequencing (WGS), enable "
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    ABSTRACT: New advances in genomic technology are being introduced at a greater speed and are revolutionizing the field of genetics for both complex and Mendelian diseases. For instance, during the past few years, genome-wide association studies (GWAS) have identified a large number of significant associations between genomic loci and movement disorders such as Parkinson's disease and progressive supranuclear palsy. GWAS are carried out through the use of high-throughput SNP genotyping arrays, which are also used to perform linkage analyses in families previously considered statistically underpowered for genetic analyses. In inherited movement disorders, using this latter technology, it has repeatedly been shown that mutations in a single gene can lead to different phenotypes, while the same clinical entity can be caused by mutations in different genes. This is being highlighted with the use of next-generation sequencing technologies and leads to the search for genes or genetic modifiers that contribute to the phenotypic expression of movement disorders. Establishing an accurate genome-epigenome-phenotype relationship is becoming a major challenge in the post-genomic research that should be facilitated through the implementation of both functional and cellular analyses.
    Frontiers in Genetics 05/2012; 3:75. DOI:10.3389/fgene.2012.00075
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    • "Recent identification of the PARK16 locus revealed a novel RAB7L1 mutation as being associated with PD ( Simó n - Sánchez et al . , 2009 ; Tucci et al . , 2010 ) . RAB7 is a member of the Rab GTPase superfamily involved in vesicle trafficking and functions at the lysosome to promote vesicle tethering and fusion . Interest - ingly , in yeast , RAB7 is activated by the HOPS complex compo - nent VPS39 , which functions as a guanine nucleotide exchange factor , and activated RAB7 directly interact"
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    ABSTRACT: Disruption of the lysosomal system has emerged as a key cellular pathway in the neurotoxicity of α-synuclein (α-syn) and the progression of Parkinson's disease (PD). A large-scale RNA interference (RNAi) screen using Caenorhabditis elegans identified VPS-41, a multidomain protein involved in lysosomal protein trafficking, as a modifier of α-syn accumulation and dopaminergic neuron degeneration (Hamamichi et al., 2008). Previous studies have shown a conserved neuroprotective function of human VPS41 (hVPS41) against PD-relevant toxins in mammalian cells and C. elegans neurons (Ruan et al., 2010). Here, we report that both the AP-3 (heterotetrameric adaptor protein complex) interaction domain and clathrin heavy-chain repeat domain are required for protecting C. elegans dopaminergic neurons from α-syn-induced neurodegeneration, as well as to prevent α-syn inclusion formation in an H4 human neuroglioma cell model. Using mutant C. elegans and neuron-specific RNAi, we revealed that hVPS41 requires both a functional AP-3 (heterotetrameric adaptor protein complex) and HOPS (homotypic fusion and vacuole protein sorting)-tethering complex to elicit neuroprotection. Interestingly, two nonsynonymous single-nucleotide polymorphisms found within the AP-3 interacting domain of hVPS41 attenuated the neuroprotective property, suggestive of putative susceptibility factors for PD. Furthermore, we observed a decrease in α-syn protein level when hVPS41 was overexpressed in human neuroglioma cells. Thus, the neuroprotective capacity of hVPS41 may be a consequence of enhanced clearance of misfolded and aggregated proteins, including toxic α-syn species. These data reveal the importance of lysosomal trafficking in maintaining cellular homeostasis in the presence of enhanced α-syn expression and toxicity. Our results support hVPS41 as a potential novel therapeutic target for the treatment of synucleinopathies like PD.
    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 02/2012; 32(6):2142-53. DOI:10.1523/JNEUROSCI.2606-11.2012 · 6.75 Impact Factor
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