The autophagy inducer SMER28 attenuates microtubule dynamics mediating neuroprotection
Abstract SMER28 originated from a screen for small molecules that act as modulators of autophagy. SMER28 enhanced the clearance of autophagic substrates such as mutant huntingtin, which was additive to rapamycin-induced autophagy. Thus, SMER28 was established as a positive regulator of autophagy act...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2022-10-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-022-20563-3 |
| _version_ | 1811257045356118016 |
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| author | Marco Kirchenwitz Stephanie Stahnke Kyra Grunau Lars Melcher Marco van Ham Klemens Rottner Anika Steffen Theresia E. B. Stradal |
| author_facet | Marco Kirchenwitz Stephanie Stahnke Kyra Grunau Lars Melcher Marco van Ham Klemens Rottner Anika Steffen Theresia E. B. Stradal |
| author_sort | Marco Kirchenwitz |
| collection | DOAJ |
| description | Abstract SMER28 originated from a screen for small molecules that act as modulators of autophagy. SMER28 enhanced the clearance of autophagic substrates such as mutant huntingtin, which was additive to rapamycin-induced autophagy. Thus, SMER28 was established as a positive regulator of autophagy acting independently of the mTOR pathway, increasing autophagosome biosynthesis and attenuating mutant huntingtin-fragment toxicity in cellular- and fruit fly disease models, suggesting therapeutic potential. Despite many previous studies, molecular mechanisms mediating SMER28 activities and its direct targets have remained elusive. Here we analyzed the effects of SMER28 on cells and found that aside from autophagy induction, it significantly stabilizes microtubules and decelerates microtubule dynamics. Moreover, we report that SMER28 displays neurotrophic and neuroprotective effects at the cellular level by inducing neurite outgrowth and protecting from excitotoxin-induced axon degeneration. Finally, we compare the effects of SMER28 with other autophagy-inducing or microtubule-stabilizing drugs: whereas SMER28 and rapamycin both induce autophagy, the latter does not stabilize microtubules, and whereas both SMER28 and epothilone B stabilize microtubules, epothilone B does not stimulate autophagy. Thus, the effect of SMER28 on cells in general and neurons in particular is based on its unique spectrum of bioactivities distinct from other known microtubule-stabilizing or autophagy-inducing drugs. |
| first_indexed | 2024-04-12T17:50:28Z |
| format | Article |
| id | doaj.art-ee54191d6781400988b8abc24f010932 |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-04-12T17:50:28Z |
| publishDate | 2022-10-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-ee54191d6781400988b8abc24f0109322022-12-22T03:22:31ZengNature PortfolioScientific Reports2045-23222022-10-0112111410.1038/s41598-022-20563-3The autophagy inducer SMER28 attenuates microtubule dynamics mediating neuroprotectionMarco Kirchenwitz0Stephanie Stahnke1Kyra Grunau2Lars Melcher3Marco van Ham4Klemens Rottner5Anika Steffen6Theresia E. B. Stradal7Department of Cell Biology, Helmholtz Centre for Infection ResearchDepartment of Cell Biology, Helmholtz Centre for Infection ResearchDepartment of Cell Biology, Helmholtz Centre for Infection ResearchDepartment of Cell Biology, Helmholtz Centre for Infection ResearchCellular Proteome Research, Helmholtz Centre for Infection ResearchDepartment of Cell Biology, Helmholtz Centre for Infection ResearchDepartment of Cell Biology, Helmholtz Centre for Infection ResearchDepartment of Cell Biology, Helmholtz Centre for Infection ResearchAbstract SMER28 originated from a screen for small molecules that act as modulators of autophagy. SMER28 enhanced the clearance of autophagic substrates such as mutant huntingtin, which was additive to rapamycin-induced autophagy. Thus, SMER28 was established as a positive regulator of autophagy acting independently of the mTOR pathway, increasing autophagosome biosynthesis and attenuating mutant huntingtin-fragment toxicity in cellular- and fruit fly disease models, suggesting therapeutic potential. Despite many previous studies, molecular mechanisms mediating SMER28 activities and its direct targets have remained elusive. Here we analyzed the effects of SMER28 on cells and found that aside from autophagy induction, it significantly stabilizes microtubules and decelerates microtubule dynamics. Moreover, we report that SMER28 displays neurotrophic and neuroprotective effects at the cellular level by inducing neurite outgrowth and protecting from excitotoxin-induced axon degeneration. Finally, we compare the effects of SMER28 with other autophagy-inducing or microtubule-stabilizing drugs: whereas SMER28 and rapamycin both induce autophagy, the latter does not stabilize microtubules, and whereas both SMER28 and epothilone B stabilize microtubules, epothilone B does not stimulate autophagy. Thus, the effect of SMER28 on cells in general and neurons in particular is based on its unique spectrum of bioactivities distinct from other known microtubule-stabilizing or autophagy-inducing drugs.https://doi.org/10.1038/s41598-022-20563-3 |
| spellingShingle | Marco Kirchenwitz Stephanie Stahnke Kyra Grunau Lars Melcher Marco van Ham Klemens Rottner Anika Steffen Theresia E. B. Stradal The autophagy inducer SMER28 attenuates microtubule dynamics mediating neuroprotection Scientific Reports |
| title | The autophagy inducer SMER28 attenuates microtubule dynamics mediating neuroprotection |
| title_full | The autophagy inducer SMER28 attenuates microtubule dynamics mediating neuroprotection |
| title_fullStr | The autophagy inducer SMER28 attenuates microtubule dynamics mediating neuroprotection |
| title_full_unstemmed | The autophagy inducer SMER28 attenuates microtubule dynamics mediating neuroprotection |
| title_short | The autophagy inducer SMER28 attenuates microtubule dynamics mediating neuroprotection |
| title_sort | autophagy inducer smer28 attenuates microtubule dynamics mediating neuroprotection |
| url | https://doi.org/10.1038/s41598-022-20563-3 |
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