TY - JOUR
T1 - Stathmin-2 loss leads to neurofilament-dependent axonal collapse driving motor and sensory denervation
AU - López-Erauskin, Jone
AU - Bravo-Hernandez, Mariana
AU - Presa, Maximiliano
AU - Baughn, Michael W.
AU - Melamed, Ze’ev
AU - Beccari, Melinda S.
AU - Agra de Almeida Quadros, Ana Rita
AU - Arnold-Garcia, Olatz
AU - Zuberi, Aamir
AU - Ling, Karen
AU - Platoshyn, Oleksandr
AU - Niño-Jara, Elkin
AU - Ndayambaje, I. Sandra
AU - McAlonis-Downes, Melissa
AU - Cabrera, Larissa
AU - Artates, Jonathan W.
AU - Ryan, Jennifer
AU - Hermann, Anita
AU - Ravits, John
AU - Bennett, C. Frank
AU - Jafar-Nejad, Paymaan
AU - Rigo, Frank
AU - Marsala, Martin
AU - Lutz, Cathleen M.
AU - Cleveland, Don W.
AU - Lagier-Tourenne, Clotilde
N1 - Publisher Copyright:
© 2023, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2024/1
Y1 - 2024/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85177562718&partnerID=8YFLogxK
U2 - 10.1038/s41593-023-01496-0
DO - 10.1038/s41593-023-01496-0
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C2 - 37996528
AN - SCOPUS:85177562718
SN - 1097-6256
VL - 27
SP - 34
EP - 47
JO - Nature Neuroscience
JF - Nature Neuroscience
IS - 1
ER -
