Stathmin-2 loss leads to neurofilament-dependent axonal collapse driving motor and sensory denervation.

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JMG, Animals, Mice, Amyotrophic Lateral Sclerosis, Axons, Denervation, DNA-Binding Proteins, Intermediate Filaments, Motor Neurons, Stathmin

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Nat Neurosci. 2023;27(1):34-47.







We are grateful to the Muscular Dystrophy Association for supporting J.L.-E. and Z.M. with MDA Development grants. We thank the UCSD Genetics Training Program and the National Institute for General Medical Sciences, T32 GM008666 for supporting M.W.B. and T32AG066596-01 for supporting M.S.B. A.R.A.A.Q is the recipient of a Postdoctoral Fellowship from the BrightFocus Foundation (grant A2022002F). This work was supported by grants from ALS Finding a Cure (to C.L.-T.) and NINDS/NIH (R01NS112503 to M.M., C.L.-T. and D.W.C., the Nomis Foundation to D.W.C., and RF1NS124203 to C.M.L., D.W.C. and C.L.-T.). The microscope core was supported by NINDS/NIH (P30NS047101). C.L.-T. is the recipient of the Araminta Broch-Healey Endowed Chair in ALS.


The mRNA transcript of the human STMN2 gene, encoding for stathmin-2 protein (also called SCG10), is profoundly impacted by TAR DNA-binding protein 43 (TDP-43) loss of function. The latter is a hallmark of several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Using a combination of approaches, including transient antisense oligonucleotide-mediated suppression, sustained shRNA-induced depletion in aging mice, and germline deletion, we show that stathmin-2 has an important role in the establishment and maintenance of neurofilament-dependent axoplasmic organization that is critical for preserving the caliber and conduction velocity of myelinated large-diameter axons. Persistent stathmin-2 loss in adult mice results in pathologies found in ALS, including reduced interneurofilament spacing, axonal caliber collapse that drives tearing within outer myelin layers, diminished conduction velocity, progressive motor and sensory deficits, and muscle denervation. These findings reinforce restoration of stathmin-2 as an attractive therapeutic approach for ALS and other TDP-43-dependent neurodegenerative diseases.