Synaptotagmin 13 is neuroprotective across motor neuron diseases

M Nizzardo,E Hedlund,N Bresolin,F Rizzo,G P Comi,S Corti,M Taiana,I Allodi,J Nijssen,V Melzi,J Aguila Benitez

doi:10.1007/s00401-020-02133-x

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.

Highlights

Amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA) are lethal neurodegenerative diseases characterized by a progressive loss of motor neurons in the spinal cord, brainstem, and cortex [9, 21]
Synaptotagmin 13 (SYT13) was among these 24 DEGs with strong preferential expression in oculomotor neurons (OMNs) (Fig. 1a–c), which we found interesting, because SYTs are vesicular trafficking proteins important for synapses
Using the probe specific for SYT13, we found that SYT13 mRNA was highly expressed in human OMNs (Fig. 1d, e, h), with lower levels in spinal motor neurons (Fig. 1f–h), validating the transcriptome data from rodents and showing the specificity of SYT13 expression in human OMNs

Summary

Introduction

Amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA) are lethal neurodegenerative diseases characterized by a progressive loss of motor neurons in the spinal cord, brainstem, and cortex [9, 21]. Some motor neurons are preserved throughout late stages of these diseases, including oculomotor neurons (OMNs), trochlear neurons and neurons in the abducens, which regulate eye movement as well as Onuf’s nuclei, which controls sphincter function This has been demonstrated in both mouse models [11, 24, 29, 32, 55] and in post-mortem tissues from patients [31, 35, 39, 60]. Both the familial (f) and sporadic (s) forms of ALS and SMA share this pattern of selective motor neuron resistance [35, 61]. Previous studies of ALS and SMA [52] suggest that elements intrinsic to motor

Methods

Results

Conclusion