STMN2 protein depletion via translation deficits and stress granules and its compensation in ALS

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, single-molecule in situ analysis of mRNA localisation and translation, and longitudinal analysis of neuronal fitness/survival, we establish TDP-43-independent mechanisms of STMN2 depletion linked to stress response. We find that human STMN2 protein is extremely labile under acute high-magnitude stress. Early in stress, STMN2 is suppressed via activated proteasomal degradation, phosphorylation and translational 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. Finally, we demonstrate that STMN2 mRNA is upregulated in non-TDP ALS such as ALS-FUS, which may compensate for translation/stress granule defects in these disease subtypes. 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 hallmarks of neurodegeneration, translation impairment and abnormal stress granules, in STMN2 depletion and reports an RNA-level compensation that fails in neurons with TDP-43 pathology. Our study supports the development of stress response targeting therapies in ALS with and without TDP-43 pathology.