STMN2 protein depletion via translation deficits and stress granules in amyotrophic lateral sclerosis
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ID: 318836
2026
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Abstract
STMN2 is an abundant neurospecific protein dysregulated in neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). We previously reported that cellular stress can lead to STMN2 loss due to TDP-43 nuclear condensation. Here, using human and murine neuronal cell models, multiple pharmacological tools, in situ single-molecule analysis of translation and RNA localisation, and longitudinal analysis of neuronal fitness/survival, we establish TDP-43-independent mechanisms of STMN2 depletion under stress. We find that human STMN2 protein level is extremely labile under acute high-magnitude stress. Early in stress, STMN2 is suppressed via activated proteasomal degradation, phosphorylation and translation repression by stress granules, independently of TDP-43 loss of function in splicing. We further show that STMN2 protein level is highly sensitive to chronic translation deficits, such as those elicited by prolonged low-grade stress. We find that low pre-stress STMN2 sensitises neuronal cells to stress-induced apoptosis, whereas moderately increased STMN2 is protective under stress. Finally, we demonstrate that STMN2 mRNA is upregulated in non-TDP ALS (ALS-FUS) models, which may compensate for translation/stress granule defects in this disease subtype. Consistent with the compensation hypothesis, STMN2 mRNA is also upregulated in the relatively spared (cortex), but not severely affected (spinal cord), CNS regions in ALS-TDP. In conclusion, our study implicates two common denominators in neurodegeneration - dysregulation of translation and stress granules - in STMN2 depletion, independent of TDP-43 loss of function. It also describes an RNA-based compensatory mechanism in ALS underling the unique vulnerability of neurons with developing TDP-43 pathology.
| Reference Key |
openalex_W7165858409
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| Authors | Brittany C S Ellis, Anna Sanchez Avila, Wan-Ping Huang, Sabin J. John, Sam Bonsall, Hodgson Rj, Vedanth Kumar, Matthew Nolan, Ryan J. H. West, Susan G. Campbell, Kurt J. De Vos, Clotilde Lagier-Tourenne, J Robin Highley, Johnathan Cooper‐Knock, Tatyana A. Shelkovnikova |
| Journal | Brain research |
| Year | 2026 |
| DOI |
10.1093/brain/awag222
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| URL | |
| Keywords | Keywords not found |
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