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

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

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.