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Acta Neuropathol. 2020 Feb 17. doi: 10.1007/s00401-020-02133-x. [Epub ahead of print]

Synaptotagmin 13 is neuroprotective across motor neuron diseases.

Author information

1
Dino Ferrari Centre, Neuroscience Section, Department of Pathophysiology and Transplantation (DEPT), University of Milan, Milan, Italy.
2
Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Neurology Unit, Via Francesco Sforza 35, 20122, Milan, Italy.
3
Department of Neuroscience, Biomedicum D7, Karolinska Institutet, Solna v. 9, 171 77, Stockholm, Sweden.
4
Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Neuromuscular and Rare Diseases Unit, Via Francesco Sforza 35, 20122, Milan, Italy.
5
Department of Neuroscience, Biomedicum D7, Karolinska Institutet, Solna v. 9, 171 77, Stockholm, Sweden. eva.hedlund@ki.se.
6
Dino Ferrari Centre, Neuroscience Section, Department of Pathophysiology and Transplantation (DEPT), University of Milan, Milan, Italy. stefania.corti@unimi.it.
7
Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Neurology Unit, Via Francesco Sforza 35, 20122, Milan, Italy. stefania.corti@unimi.it.

Abstract

In amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA), spinal and lower brainstem motor neurons degenerate, but some motor neuron subtypes are spared, including oculomotor neurons (OMNs). The mechanisms responsible for this selective degeneration are largely unknown, but the molecular signatures of resistant and vulnerable motor neurons are distinct and offer clues to neuronal resilience and susceptibility. Here, we demonstrate that healthy OMNs preferentially express Synaptotagmin 13 (SYT13) compared to spinal motor neurons. In end-stage ALS patients, SYT13 is enriched in both OMNs and the remaining relatively resilient spinal motor neurons compared to controls. Overexpression of SYT13 in ALS and SMA patient motor neurons in vitro improves their survival and increases axon lengths. Gene therapy with Syt13 prolongs the lifespan of ALS mice by 14% and SMA mice by 50% by preserving motor neurons and delaying muscle denervation. SYT13 decreases endoplasmic reticulum stress and apoptosis of motor neurons, both in vitro and in vivo. Thus, SYT13 is a resilience factor that can protect motor neurons and a candidate therapeutic target across motor neuron diseases.

PMID:
32065260
DOI:
10.1007/s00401-020-02133-x

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