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Biological Sciences - Article
I-Fan Wang
Garage Brain Science
Corresponding Author
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Spinal muscular atrophy (SMA) causes the loss of motor neurons and progressive muscle weakness. In 95% of patients with SMA, both alleles of the survival motor neuron 1 (SMN1) gene are deleted or the gene contains missense mutations. A nearly identical copy of SMN1, SMN2, is normally expressed but is unable to compensate for the loss of SMN1 due to the deletion of exon 7. Here, we demonstrated that conformational editing of the SMN2 protein triggers effective phase separation of SMN2 proteins and rescues SMA. We found that SMN1 contains a prion-like LC domain at exons 6-7, which drives liquid-liquid phase separation (LLPS) and further discovered an LLPS activator of gems, baicalein. Using baicalein, we reinvented SMN2 proteins into a competent prion-like conformation to restore the prion-like functions of SMN1 and effectively rescue SMA mice. Our study suggests that the impaired prion-like activity of SMN1 is the root cause of SMA and provides a drug candidate for SMA and phase separation-deficient diseases.
Keywords
survival motor neuron (SMN) proteins, spinal muscular atrophy (SMA), prion-like LC domain, liquid-liquid phase separation (LLPS), gems and Baicalein.
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This is a list of supplementary files associated with this preprint. Click to download.
- FigS1.jpg
Extended Data Fig. 1
- FigS2.0.jpg
Extended Data Fig. 2
- FigS3.jpg
Extended Data Fig. 3
- FigS4.jpg
Extended Data Fig. 4
- WangSI.docx
supplementary information
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A new preprint design is coming!
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This is a preprint, a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
Biological Sciences - Article
I-Fan Wang
Garage Brain Science
Corresponding Author
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
History
CURRENT STATUS: Posted
Version 1
Posted 11 Jun, 2021
No community comments so far
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
License:
This work is licensed under a CC BY 4.0 License. Read Full License
Spinal muscular atrophy (SMA) causes the loss of motor neurons and progressive muscle weakness. In 95% of patients with SMA, both alleles of the survival motor neuron 1 (SMN1) gene are deleted or the gene contains missense mutations. A nearly identical copy of SMN1, SMN2, is normally expressed but is unable to compensate for the loss of SMN1 due to the deletion of exon 7. Here, we demonstrated that conformational editing of the SMN2 protein triggers effective phase separation of SMN2 proteins and rescues SMA. We found that SMN1 contains a prion-like LC domain at exons 6-7, which drives liquid-liquid phase separation (LLPS) and further discovered an LLPS activator of gems, baicalein. Using baicalein, we reinvented SMN2 proteins into a competent prion-like conformation to restore the prion-like functions of SMN1 and effectively rescue SMA mice. Our study suggests that the impaired prion-like activity of SMN1 is the root cause of SMA and provides a drug candidate for SMA and phase separation-deficient diseases.
Figure 1
Figure 2
Figure 3
There is NO Competing Interest.
This is a list of supplementary files associated with this preprint. Click to download.
- FigS1.jpg
Extended Data Fig. 1
- FigS2.0.jpg
Extended Data Fig. 2
- FigS3.jpg
Extended Data Fig. 3
- FigS4.jpg
Extended Data Fig. 4
- WangSI.docx
supplementary information
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