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Alpha-synuclein abundance and localization are regulated by the RNA-binding protein PUMILIO1
Maximilian Cabaj1, Pietro G Mazzara1, Zachary A Gaertner2
1Department of Genetics and Development, Columbia University Irving Medical Center, New York, NY, USA.
Cell Reports
|August 15, 2025
Summary
The RNA-binding protein PUM1 regulates alpha-synuclein (SNCA) levels in Parkinson's disease models. PUM1 targeting offers a potential therapeutic strategy for synucleinopathies.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Alpha-synuclein (SNCA) aggregation is a hallmark of Parkinson's disease (PD) and other synucleinopathies.
- The precise regulatory mechanisms controlling SNCA levels in vivo remain incompletely understood.
Purpose of the Study:
- To investigate the role of RNA-binding protein PUM1 in regulating SNCA expression.
- To explore PUM1's potential as a therapeutic target for synucleinopathies.
Main Methods:
- Investigated PUM1 binding to SNCA 3' UTR in human and mouse cells.
- Utilized induced neurons from PD patients with SNCA locus triplication.
- Performed microfluidic chamber experiments to assess SNCA distribution.
- Analyzed PUM1 variants in PD patient databases.
Main Results:
- PUM1 directly binds to the SNCA 3' UTR.
- Restoring PUM1 levels in patient-derived neurons normalized SNCA mRNA and protein.
- PUM1 regulates SNCA isoform suppression and axonal transport.
- PUM1 is required for miR-7-mediated SNCA regulation.
- Identified PD patients with PUM1 variants impacting RNA binding.
Conclusions:
- PUM1 is a key regulator of SNCA expression and localization.
- PUM1 modulation presents a novel therapeutic avenue for synucleinopathies.
- Understanding PUM1-SNCA interactions is crucial for developing new PD treatments.
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