Synaptotagmin 13 is neuroprotective across motor neuron diseases.

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.

journal_name

Acta Neuropathol

journal_title

Acta neuropathologica

authors

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

doi

10.1007/s00401-020-02133-x

subject

Has Abstract

pub_date

2020-05-01 00:00:00

pages

837-853

issue

5

eissn

0001-6322

issn

1432-0533

pii

10.1007/s00401-020-02133-x

journal_volume

139

pub_type

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