Alpha-synuclein abundance and localization are regulated by the RNA-binding protein PUMILIO1
Summary: The protein α-synuclein, encoded by SNCA, accumulates in Parkinson’s disease (PD) and other synucleinopathies for reasons that remain unclear. Here, we investigated whether SNCA is regulated in vivo by the RNA-binding protein PUM1. We establish that PUM1 binds to SNCA’s 3′ UTR in mouse and...
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Elsevier
2025-08-01
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| Series: | Cell Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124725009167 |
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| author | Maximilian Cabaj Pietro G. Mazzara Zachary A. Gaertner Ruizhi Wang Michaela M. Pauers Lisa K. Randolph Cláudio Gouveia Roque Sean Feeney Serena Raimo Nicola de Prisco Alexei Chemiakine Xinyuan Wang Ravi K. Singh Swetha Rajasekaran Hari K. Yalamanchili Wayne Miles Kristin Baldwin Chaolin Zhang Matthew B. Harms Vikram Khurana Vicky Brandt Ulrich Hengst Rajeshwar Awatramani Vincenzo A. Gennarino |
| author_facet | Maximilian Cabaj Pietro G. Mazzara Zachary A. Gaertner Ruizhi Wang Michaela M. Pauers Lisa K. Randolph Cláudio Gouveia Roque Sean Feeney Serena Raimo Nicola de Prisco Alexei Chemiakine Xinyuan Wang Ravi K. Singh Swetha Rajasekaran Hari K. Yalamanchili Wayne Miles Kristin Baldwin Chaolin Zhang Matthew B. Harms Vikram Khurana Vicky Brandt Ulrich Hengst Rajeshwar Awatramani Vincenzo A. Gennarino |
| author_sort | Maximilian Cabaj |
| collection | DOAJ |
| description | Summary: The protein α-synuclein, encoded by SNCA, accumulates in Parkinson’s disease (PD) and other synucleinopathies for reasons that remain unclear. Here, we investigated whether SNCA is regulated in vivo by the RNA-binding protein PUM1. We establish that PUM1 binds to SNCA’s 3′ UTR in mouse and human cells. In induced neurons from patients with SNCA locus triplication, PUM1 mRNA levels are lower than in healthy controls, but increasing PUM1 normalizes both SNCA mRNA and α-synuclein protein levels, largely by suppressing the long 3′ UTR SNCA isoform. In microfluidic chamber experiments, silencing PUM1 causes a redistribution of SNCA between the soma and axons. We also show that the previously described miR-7 regulation of SNCA mRNA requires PUM1. Lastly, we report finding several individuals with PD in clinical databases bearing variants in PUM1 that affect its RNA-binding ability. Understanding how RNA-binding proteins regulate α-synuclein could lead to viable new therapies for synucleinopathies. |
| format | Article |
| id | doaj-art-90bd31d64482437dbca10f3ee4f1aa29 |
| institution | DOAJ |
| issn | 2211-1247 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj-art-90bd31d64482437dbca10f3ee4f1aa292025-08-20T03:05:44ZengElsevierCell Reports2211-12472025-08-0144811614510.1016/j.celrep.2025.116145Alpha-synuclein abundance and localization are regulated by the RNA-binding protein PUMILIO1Maximilian Cabaj0Pietro G. Mazzara1Zachary A. Gaertner2Ruizhi Wang3Michaela M. Pauers4Lisa K. Randolph5Cláudio Gouveia Roque6Sean Feeney7Serena Raimo8Nicola de Prisco9Alexei Chemiakine10Xinyuan Wang11Ravi K. Singh12Swetha Rajasekaran13Hari K. Yalamanchili14Wayne Miles15Kristin Baldwin16Chaolin Zhang17Matthew B. Harms18Vikram Khurana19Vicky Brandt20Ulrich Hengst21Rajeshwar Awatramani22Vincenzo A. Gennarino23Department of Genetics and Development, Columbia University Irving Medical Center, New York, NY, USADepartment of Genetics and Development, Columbia University Irving Medical Center, New York, NY, USADepartment of Neurology, Northwestern University, Chicago, IL, USADepartment of Pathology and Cell Biology, Columbia University Vagelos College of Physicians and Surgeons, New York, NY, USA; Department of Neurology, Columbia University Irving Medical Center, New York, NY, USADepartment of Pathology and Cell Biology, Columbia University Vagelos College of Physicians and Surgeons, New York, NY, USADoctoral Program in Neurobiology and Behavior, Columbia University, New York, NY, USATaub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University Vagelos College of Physicians and Surgeons, New York, NY, USADoctoral Program in Neurobiology and Behavior, Columbia University, New York, NY, USADepartment of Genetics and Development, Columbia University Irving Medical Center, New York, NY, USADepartment of Genetics and Development, Columbia University Irving Medical Center, New York, NY, USADepartment of Genetics and Development, Columbia University Irving Medical Center, New York, NY, USADivision of Movement Disorders, American Parkinson Disease Association (APDA) Center for Advanced Research and MSA Center of Excellence, Department of Neurology, Brigham and Women’s Hospital, Boston, MA, USA; Harvard Stem Cell Institute, Cambridge, MA, USADepartment of Pharmacological and Pharmaceutical Sciences, College of Pharmacy University of Houston, Houston, TX, USADepartment of Cancer Biology and Genetics, The Ohio State University, 460 West 12th Avenue, Columbus, OH 43210, USA; The Ohio State University Comprehensive Cancer Center, The Ohio State University, 460 West 12th Avenue, Columbus, OH 43210, USAJan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, TX, USA; USDA/ARS Children’s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USADepartment of Cancer Biology and Genetics, The Ohio State University, 460 West 12th Avenue, Columbus, OH 43210, USA; The Ohio State University Comprehensive Cancer Center, The Ohio State University, 460 West 12th Avenue, Columbus, OH 43210, USADepartment of Genetics and Development, Columbia University Irving Medical Center, New York, NY, USADepartment of Systems Biology, Columbia University Irving Medical Center, New York, NY, USA; Department of Biochemistry and Molecular Biophysics, Columbia University Irving Medical Center, New York, NY, USADepartment of Neurology, Columbia University Irving Medical Center, New York, NY, USADivision of Movement Disorders, American Parkinson Disease Association (APDA) Center for Advanced Research and MSA Center of Excellence, Department of Neurology, Brigham and Women’s Hospital, Boston, MA, USA; Harvard Stem Cell Institute, Cambridge, MA, USA; Harvard Medical School, Boston, MA, USA; The Broad Institute of MIT and Harvard, Cambridge, MA, USADepartment of Genetics and Development, Columbia University Irving Medical Center, New York, NY, USADepartment of Pathology and Cell Biology, Columbia University Vagelos College of Physicians and Surgeons, New York, NY, USA; Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University Vagelos College of Physicians and Surgeons, New York, NY, USADepartment of Neurology, Northwestern University, Chicago, IL, USADepartment of Genetics and Development, Columbia University Irving Medical Center, New York, NY, USA; Department of Neurology, Columbia University Irving Medical Center, New York, NY, USA; Department of Pediatrics, Columbia University Irving Medical Center, New York, NY, USA; Columbia Stem Cell Initiative, Columbia University Irving Medical Center, New York, NY, USA; Initiative for Columbia Ataxia and Tremor, Columbia University Irving Medical Center, New York, NY, USA; Corresponding authorSummary: The protein α-synuclein, encoded by SNCA, accumulates in Parkinson’s disease (PD) and other synucleinopathies for reasons that remain unclear. Here, we investigated whether SNCA is regulated in vivo by the RNA-binding protein PUM1. We establish that PUM1 binds to SNCA’s 3′ UTR in mouse and human cells. In induced neurons from patients with SNCA locus triplication, PUM1 mRNA levels are lower than in healthy controls, but increasing PUM1 normalizes both SNCA mRNA and α-synuclein protein levels, largely by suppressing the long 3′ UTR SNCA isoform. In microfluidic chamber experiments, silencing PUM1 causes a redistribution of SNCA between the soma and axons. We also show that the previously described miR-7 regulation of SNCA mRNA requires PUM1. Lastly, we report finding several individuals with PD in clinical databases bearing variants in PUM1 that affect its RNA-binding ability. Understanding how RNA-binding proteins regulate α-synuclein could lead to viable new therapies for synucleinopathies.http://www.sciencedirect.com/science/article/pii/S2211124725009167CP: NeuroscienceCP: Molecular biology |
| spellingShingle | Maximilian Cabaj Pietro G. Mazzara Zachary A. Gaertner Ruizhi Wang Michaela M. Pauers Lisa K. Randolph Cláudio Gouveia Roque Sean Feeney Serena Raimo Nicola de Prisco Alexei Chemiakine Xinyuan Wang Ravi K. Singh Swetha Rajasekaran Hari K. Yalamanchili Wayne Miles Kristin Baldwin Chaolin Zhang Matthew B. Harms Vikram Khurana Vicky Brandt Ulrich Hengst Rajeshwar Awatramani Vincenzo A. Gennarino Alpha-synuclein abundance and localization are regulated by the RNA-binding protein PUMILIO1 Cell Reports CP: Neuroscience CP: Molecular biology |
| title | Alpha-synuclein abundance and localization are regulated by the RNA-binding protein PUMILIO1 |
| title_full | Alpha-synuclein abundance and localization are regulated by the RNA-binding protein PUMILIO1 |
| title_fullStr | Alpha-synuclein abundance and localization are regulated by the RNA-binding protein PUMILIO1 |
| title_full_unstemmed | Alpha-synuclein abundance and localization are regulated by the RNA-binding protein PUMILIO1 |
| title_short | Alpha-synuclein abundance and localization are regulated by the RNA-binding protein PUMILIO1 |
| title_sort | alpha synuclein abundance and localization are regulated by the rna binding protein pumilio1 |
| topic | CP: Neuroscience CP: Molecular biology |
| url | http://www.sciencedirect.com/science/article/pii/S2211124725009167 |
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