Synaptotagmin 13 is neuroprotective across motor neuron diseases

Nizzardo, Monica; Taiana, Michela; Rizzo, Federica; Benitez, Julio Aguila; Nijssen, Jik; Allodi, Ilary; Melzi, Valentina; Bresolin, Nereo; Comi, Giacomo Pietro; Hedlund, Eva; Corti, Stefania

doi:10.1007/s00401-020-02133-x

Cited by 35 publications

(37 citation statements)

References 68 publications

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“…Thus, stabilization of V1 inhibitory inputs could potentially reduce the stress responses in motor neurons. Several attempts have been directed to stabilize the neuromuscular synapses formed by motor neurons and their target muscles 52, 53, 54, 55 . Drugs known to reduce hyperexcitability directly in motor neurons as the FDA approved Riluzole and Retigabine 56 have been shown to improve motor neuron survival in ALS.…”

Section: Discussionmentioning

confidence: 99%

Locomotor deficits in ALS mice are paralleled by loss of V1-interneuron-connections onto fast motor neurons

Allodi

Montañana-Rosell

Selvan

et al. 2020

Preprint

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ALS is characterized by progressive inability to execute movements. Motor neurons innervating fast-twitch muscle fibers exhibit preferential degeneration. The reason for differential vulnerability of fast motor neurons, and its consequence on motor output is not known. Here, we show that fast motor neurons receive more inhibitory synaptic inputs than slow motor neurons, and loss of inhibitory synapses onto fast motor neurons precedes disease progression in the SOD1 G93A mouse model of ALS. Loss of inhibitory synapses on fast motor neurons is accounted for by a loss of synapses from inhibitory V1 spinal interneurons. Deficits in V1-motor neuron connectivity appear prior to motor neuron death and are paralleled by development of specific SOD1 G93A locomotor deficits. These distinct SOD1 G93A locomotor deficits are phenocopied by silencing of inhibitory V1 spinal interneurons in wild-type mice. Silencing inhibitory V1 spinal interneurons does not exacerbate SOD1 G93A locomotor deficits, suggesting phenotypic pathway interaction. Our study identifies a potential cell non-autonomous source of motor neuronal vulnerability in ALS, and links ALS-induced changes in locomotor phenotypes to inhibitory V1 interneurons.

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Section: Discussionmentioning

confidence: 99%

Locomotor deficits in ALS mice are paralleled by loss of V1-interneuron-connections onto fast motor neurons

Allodi

Montañana-Rosell

Selvan

et al. 2020

Preprint

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show abstract

“…Furthermore, an interesting strategy published by Nizzardo et al [ 147 ] took advantage of the known pathophysiological processes in motor neuron disorders (MND) to perform a comprehensive transcriptomic analysis. In particular, the authors started from the observation that specific types of MNs are spared during the progression of the MND, like SMA and ALS.…”

Section: Strategies For the Discoveries Of Novel Biomarkers Towardmentioning

confidence: 99%

“…In particular, the authors started from the observation that specific types of MNs are spared during the progression of the MND, like SMA and ALS. They then compared the transcriptomic profile of affected MNs of the brainstem and spinal cord with the rather unaffected ocular MNs in ALS [ 147 ]. This approach led to the identification of several differentially expressed genes (DEGs), including synaptotagmin, which was demonstrated to be a neuroprotective protein in ALS.…”

Section: Strategies For the Discoveries Of Novel Biomarkers Towardmentioning

confidence: 99%

The Identification of Novel Biomarkers Is Required to Improve Adult SMA Patient Stratification, Diagnosis and Treatment

Smeriglio

Langard

Querin

et al. 2020

JPM

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Spinal muscular atrophy (SMA) is currently classified into five different subtypes, from the most severe (type 0) to the mildest (type 4) depending on age at onset, best motor function achieved, and copy number of the SMN2 gene. The two recent approved treatments for SMA patients revolutionized their life quality and perspectives. However, upon treatment with Nusinersen, the most widely administered therapy up to date, a high degree of variability in therapeutic response was observed in adult SMA patients. These data, together with the lack of natural history information and the wide spectrum of disease phenotypes, suggest that further efforts are needed to develop precision medicine approaches for all SMA patients. Here, we compile the current methods for functional evaluation of adult SMA patients treated with Nusinersen. We also present an overview of the known molecular changes underpinning disease heterogeneity. We finally highlight the need for novel techniques, i.e., -omics approaches, to capture phenotypic differences and to understand the biological signature in order to revise the disease classification and device personalized treatments.

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“…SYT13 binds to cellular membranes in a calcium-independent fashion to mediate the transport of biomolecules. 18 , 19 , 20 Our previous pattern-specific transcriptome analysis of metastasis found that SYT13 is specifically expressed in patients with peritoneal metastasis of gastric cancer. 6 Furthermore, our present immunohistochemical (IHC) analysis of an institutional cohort and expression analysis of two external cohorts confirm our previous study, and here, we show that tissue expression of SYT13 was significantly associated with peritoneal metastasis and poor prognosis of patients in all cohorts.…”

Section: Discussionmentioning

confidence: 99%

Amido-Bridged Nucleic Acid-Modified Antisense Oligonucleotides Targeting SYT13 to Treat Peritoneal Metastasis of Gastric Cancer

Kanda

Kasahara

Shimizu

et al. 2020

Molecular Therapy - Nucleic Acids

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Patients with peritoneal metastasis of gastric cancer have dismal prognosis, mainly because of inefficient systemic delivery of drugs to peritoneal tumors. We aimed to develop an intraperitoneal treatment strategy using amido-bridged nucleic acid (AmNA)-modified antisense oligonucleotides (ASOs) targeting synaptotagmin XIII ( SYT13 ) and to identify the function of SYT13 in gastric cancer cells. We screened 71 candidate oligonucleotide sequences according to SYT13 -knockdown efficacy, in vitro activity, and off-target effects. We evaluated the effects of SYT13 knockdown on cellular functions and signaling pathways, as well as the effects of intraperitoneal administration to mice of AmNA-modified anti-SYT13 ASOs. We selected the ASOs (designated hSYT13-4378 and hSYT13-4733) with the highest knockdown efficiencies and lowest off-target effects and determined their abilities to inhibit cellular functions associated with the metastatic potential of gastric cancer cells. We found that SYT13 interfered with focal adhesion kinase (FAK)-mediated intracellular signals. Intraperitoneal administration of hSYT13-4378 and hSYT13-4733 in a mouse xenograft model of metastasis inhibited the formation of peritoneal nodules and significantly increased survival. Reversible, dose- and sequence-dependent liver damage was induced by ASO treatment without causing abnormal morphological and histological changes in the brain. Intra-abdominal administration of AmNA-modified anti-SYT13 ASOs represents a promising strategy for treating peritoneal metastasis of gastric cancer.

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Synaptotagmin 13 is neuroprotective across motor neuron diseases

Cited by 35 publications

References 68 publications

Locomotor deficits in ALS mice are paralleled by loss of V1-interneuron-connections onto fast motor neurons

Locomotor deficits in ALS mice are paralleled by loss of V1-interneuron-connections onto fast motor neurons

The Identification of Novel Biomarkers Is Required to Improve Adult SMA Patient Stratification, Diagnosis and Treatment

Amido-Bridged Nucleic Acid-Modified Antisense Oligonucleotides Targeting SYT13 to Treat Peritoneal Metastasis of Gastric Cancer

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