Cyclin-G-associated kinase modifies alpha-synuclein expression levels and toxicity in Parkinson's disease: results from the GenePD Study
Although family history is a well-established risk factor for Parkinson's disease (PD), fewer than 5% of PD cases can be attributed to known genetic mutations. The etiology for the remainder of PD cases is unclear; however, neuronal accumulation of the protein α-synuclein is common to nearly al...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | en_US |
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Oxford University Press
2011
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| Online Access: | http://hdl.handle.net/1721.1/65570 https://orcid.org/0000-0003-1307-882X |
| _version_ | 1811093814067068928 |
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| author | Dumitriu, Alexandra Pacheco, Chris D. Wilk, Jemma B. Strathearn, Katherine E. Latourelle, Jeanne C. Goldwurm, Stefano Pezzoli, Gianni Rochet, Jean-Christophe Lindquist, Susan Myers, Richard H. |
| author2 | move to dc.description.sponsorship |
| author_facet | move to dc.description.sponsorship Dumitriu, Alexandra Pacheco, Chris D. Wilk, Jemma B. Strathearn, Katherine E. Latourelle, Jeanne C. Goldwurm, Stefano Pezzoli, Gianni Rochet, Jean-Christophe Lindquist, Susan Myers, Richard H. |
| author_sort | Dumitriu, Alexandra |
| collection | MIT |
| description | Although family history is a well-established risk factor for Parkinson's disease (PD), fewer than 5% of PD cases can be attributed to known genetic mutations. The etiology for the remainder of PD cases is unclear; however, neuronal accumulation of the protein α-synuclein is common to nearly all patients, implicating pathways that influence α-synuclein in PD pathogenesis. We report a genome-wide significant association (P = 3.97 × 10−8) between a polymorphism, rs1564282, in the cyclin-G-associated kinase (GAK) gene and increased PD risk, with a meta-analysis odds ratio of 1.48. This association result is based on the meta-analysis of three publicly available PD case–control genome-wide association study and genotyping from a new, independent Italian cohort. Microarray expression analysis of post-mortem frontal cortex from PD and control brains demonstrates a significant association between rs1564282 and higher α-synuclein expression, a known cause of early onset PD. Functional knockdown of GAK in cell culture causes a significant increase in toxicity when α-synuclein is over-expressed. Furthermore, knockdown of GAK in rat primary neurons expressing the A53T mutation of α-synuclein, a well-established model for PD, decreases cell viability. These observations provide evidence that GAK is associated with PD risk and suggest that GAK and α-synuclein interact in a pathway involved in PD pathogenesis. The GAK protein, a serine/threonine kinase, belongs to a family of proteins commonly targeted for drug development. This, combined with GAK's observed relationship to the levels of α-synuclein expression and toxicity, suggests that the protein is an attractive therapeutic target for the treatment of PD. |
| first_indexed | 2024-09-23T15:50:45Z |
| format | Article |
| id | mit-1721.1/65570 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T15:50:45Z |
| publishDate | 2011 |
| publisher | Oxford University Press |
| record_format | dspace |
| spelling | mit-1721.1/655702022-09-29T16:32:24Z Cyclin-G-associated kinase modifies alpha-synuclein expression levels and toxicity in Parkinson's disease: results from the GenePD Study Dumitriu, Alexandra Pacheco, Chris D. Wilk, Jemma B. Strathearn, Katherine E. Latourelle, Jeanne C. Goldwurm, Stefano Pezzoli, Gianni Rochet, Jean-Christophe Lindquist, Susan Myers, Richard H. move to dc.description.sponsorship Massachusetts Institute of Technology. Department of Biology Lindquist, Susan Lindquist, Susan Although family history is a well-established risk factor for Parkinson's disease (PD), fewer than 5% of PD cases can be attributed to known genetic mutations. The etiology for the remainder of PD cases is unclear; however, neuronal accumulation of the protein α-synuclein is common to nearly all patients, implicating pathways that influence α-synuclein in PD pathogenesis. We report a genome-wide significant association (P = 3.97 × 10−8) between a polymorphism, rs1564282, in the cyclin-G-associated kinase (GAK) gene and increased PD risk, with a meta-analysis odds ratio of 1.48. This association result is based on the meta-analysis of three publicly available PD case–control genome-wide association study and genotyping from a new, independent Italian cohort. Microarray expression analysis of post-mortem frontal cortex from PD and control brains demonstrates a significant association between rs1564282 and higher α-synuclein expression, a known cause of early onset PD. Functional knockdown of GAK in cell culture causes a significant increase in toxicity when α-synuclein is over-expressed. Furthermore, knockdown of GAK in rat primary neurons expressing the A53T mutation of α-synuclein, a well-established model for PD, decreases cell viability. These observations provide evidence that GAK is associated with PD risk and suggest that GAK and α-synuclein interact in a pathway involved in PD pathogenesis. The GAK protein, a serine/threonine kinase, belongs to a family of proteins commonly targeted for drug development. This, combined with GAK's observed relationship to the levels of α-synuclein expression and toxicity, suggests that the protein is an attractive therapeutic target for the treatment of PD. Robert P. & Judith N. Goldberg Foundation William N. & Bernice E. Bumpus Foundation Howard Hughes Medical Institute (Collaborative Innovation Award) National Science Foundation (U.S.) (R01-NS036711) 2011-08-31T16:46:58Z 2011-08-31T16:46:58Z 2011-01 2011-01 Article http://purl.org/eprint/type/JournalArticle 0964-6906 1460-2083 http://hdl.handle.net/1721.1/65570 Dumitriu, A. et al. “Cyclin-G-associated Kinase Modifies -synuclein Expression Levels and Toxicity in Parkinson’s Disease: Results from the GenePD Study.” Human Molecular Genetics 20.8 (2011) : 1478-1487. https://orcid.org/0000-0003-1307-882X en_US http://dx.doi.org/10.1093/hmg/ddr026 Human Molecular Genetics Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf Oxford University Press Oxford Journals |
| spellingShingle | Dumitriu, Alexandra Pacheco, Chris D. Wilk, Jemma B. Strathearn, Katherine E. Latourelle, Jeanne C. Goldwurm, Stefano Pezzoli, Gianni Rochet, Jean-Christophe Lindquist, Susan Myers, Richard H. Cyclin-G-associated kinase modifies alpha-synuclein expression levels and toxicity in Parkinson's disease: results from the GenePD Study |
| title | Cyclin-G-associated kinase modifies alpha-synuclein expression levels and toxicity in Parkinson's disease: results from the GenePD Study |
| title_full | Cyclin-G-associated kinase modifies alpha-synuclein expression levels and toxicity in Parkinson's disease: results from the GenePD Study |
| title_fullStr | Cyclin-G-associated kinase modifies alpha-synuclein expression levels and toxicity in Parkinson's disease: results from the GenePD Study |
| title_full_unstemmed | Cyclin-G-associated kinase modifies alpha-synuclein expression levels and toxicity in Parkinson's disease: results from the GenePD Study |
| title_short | Cyclin-G-associated kinase modifies alpha-synuclein expression levels and toxicity in Parkinson's disease: results from the GenePD Study |
| title_sort | cyclin g associated kinase modifies alpha synuclein expression levels and toxicity in parkinson s disease results from the genepd study |
| url | http://hdl.handle.net/1721.1/65570 https://orcid.org/0000-0003-1307-882X |
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