ALS and SMA: study of molecular mechanisms in resistant neurons identifies a new potential therapeutic target

SYT13 is an oculomotor restricted gene, identified as possible disease modifier of Amyotrophic Lateral Sclerosis and Spinal Muscular Atrophy (SMA), by the researchers of the Centro Dino Ferrari, University of Milan, IRCCS Fondazione Ca’ Granda, Ospedale Maggiore Policlinico and Karolinska Institutet (Sweden). The study was published in eminent journal Acta Neuropathologica journal in February 2020.

SMA and ALS are serious neurodegenerative diseases, characterized by the death of motor neurons in the Central Nervous System (CNS), the neurons that control skeletal muscles and thus voluntary movements. These diseases cause progressive weakness, muscle atrophy, deficiency in swallowing and difficulty in breathing with premature death. No effective therapies are available for ALS while the approved drugs for SMA aiming at rescuing SMN protein defect are effective only if administered very early during the disease course.

However in ALS and SMA not all motor neurons degenerate, but some subtypes are spared, in particular oculomotor neurons (OMNs), the cells that govern eye movements. The mechanisms responsible for this selective degeneration are largely unknown, but the molecular signatures of resistant and vulnerable motor neurons are distinct and might offer clues on neuronal resilience and susceptibility. In this work, we demonstrate that OMNs preferentially express Synaptotagmin 13 (SYT13) compared to vulnerable spinal motor neurons. Overexpression of SYT13 in ALS and SMA patient reprogrammed motor neurons, in vitro, improves their survival and increases axon lengths. Gene therapy with Syt13 prolongs the lifespan of ALS and SMA mice by preserving motor neurons and delaying muscle denervation. Likely, 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 therefore a candidate therapeutic target for motor neuron diseases.

Nonetheless, a deeper understanding of the molecular mechanisms underlying SYT13 effects is needed to improve and allow translation in humans of this therapeutic strategy. Moreover, comparative gene expression in OMNs and vulnerable spinal cord motor neurons might help to identify new therapeutic targets for ALS/SMA.

Prof. Corti, M.D., Ph.D. chief of the Neural Stem Cell Laboratory in the Neuroscience Division, Department of Pathophysiology and Transplantation, and Prof. Eva Hedlund Ph.D., Karolinska Institute are co-senior authors in the research. The research group included also members of Corti lab and Hedlund Lab and researchers of the Centro Dino Ferrari, University of Milan, IRCCS Fondazione Ca’ Granda, Ospedale Maggiore Policlinico.

A complex analysis of gene expression, carried out in resistant and vulnerable motor neurons, allowed the identification of additional potential therapeutic genes for ALS/SMA”- Dr. Monica Nizzardo, first author of this study, said.

The research showed that increasing the expression of SYT3 improved the disease phenotype in patient cells, as well as in ALS/SMA murine models.

“This remarkable finding”, Prof. Corti concluded, “underlines the need to deepen the knowledge on dichotomous vulnerability/resistance mechanisms in ALS/SMA motor neurons to identify new molecular targets for future therapeutic strategies”.

The research was financed by the EU Joint Programme Neurodegenerative Disease (JPND), the Thierry Latran Foundation, the Swedish Research Council, the Söderberg Foundation, the Åhlén Foundation, the Birgit Backmark endowment for ALS research at Karolinska Institutet in memory of Hans and Nils Backmark, the Ulla-Carin Lindquist Foundation for ALS Research, the Björklund Fund, the Swedish Society for Medical Research, the Cariplo Foundation, the Italian Ministry of Health,Telethon, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico and Karolinska Institutet and was supported by Associazione Centro Dino Ferrari.

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