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

• DOI: 10.1101/2022.12.11.519794
• Publication Date: 2022-12-12T19:30:14Z
• Authors: Jone Lopez-Erauskin; Mariana Bravo-Her...; Maximiliano Presa; Michael W. Baughn; Ze’ev Melamed; Melinda S. Beccari; Ana Rita Agra de ...; Aamir Zuberi; Karen Ling; Oleksandr Platoshyn; Elkin Niño-Jara; I. Sandra Ndayambaje; Olatz Arnold-Garcia; Melissa McAlonis-...; Larissa Cabrera; Jonathan W. Artates; Jennifer Ryan; Frank Bennett; Paymaan Jafar-nejad; Frank Rigo; Martin Marsala; Cathleen M. Lutz; Don W. Cleveland; Clotilde Lagier-T...
• Keywords: Stathmin; Neurofilament

Abstract The human mRNA most affected by TDP-43 loss-of-function is transcribed from the STMN2 gene and encodes stathmin-2 (also known as SCG10), whose loss a neurodegenerative disease hallmark. Here using multiple in vivo approaches, including transient antisense oligonucleotide (ASO)-mediated suppression, chronic shRNA-mediated depletion aging mice, germline deletion, we establish to be essential for acquisition maintenance of neurofilament-dependent structuring axoplasm critical maintaining diameter conduction velocity large-myelinated axons. Sustained an otherwise mature adult nervous system demonstrated over time course eight months initiate drive motor neuron that includes 1) shrinkage inter-neurofilament spacing required produce three-dimensional space filling array defines axonal caliber, 2) collapse caliber with tearing outer myelin layers, 3) reduced velocity, 4) progressive sensory deficits (including reduction pain transducing neuropeptide CGRP), 5) muscle denervation. Demonstration itself sufficient trigger reinforces restoration attractive therapeutic approach TDP-43-dependent neurodegeneration, fatal ALS.