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

Jone López-Erauskin, Mariana Bravo-Hernandez, Maximiliano Presa, Michael W. Baughn, Ze’ev Melamed, Melinda S. Beccari, Ana Rita Agra de Almeida Quadros, Olatz Arnold-Garcia, Aamir Zuberi, Karen Ling, Oleksandr Platoshyn, Elkin Niño-Jara, I. Sandra Ndayambaje, Melissa McAlonis-Downes, Larissa Cabrera, Jonathan W. Artates, Jennifer Ryan, Anita Hermann, John Ravits, C. Frank BennettPaymaan Jafar-Nejad, Frank Rigo, Martin Marsala, Cathleen M. Lutz*, Don W. Cleveland*, Clotilde Lagier-Tourenne*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

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.

Original languageAmerican English
Pages (from-to)34-47
Number of pages14
JournalNature Neuroscience
Volume27
Issue number1
DOIs
StatePublished - Jan 2024

Bibliographical note

Publisher Copyright:
© 2023, The Author(s), under exclusive licence to Springer Nature America, Inc.

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