PUBLICATION

INaP selective inhibition reverts precocious inter- and motorneurons hyperexcitability in the Sod1-G93R zebrafish ALS model

Authors

Benedetti, L., Ghilardi, A., Rottoli, E., De Maglie, M., Prosperi, L., Perego, C., Baruscotti, M., Bucchi, A., Del Giacco, L., Francolini, M.

ID

ZDB-PUB-160417-10

Date

2016

Source

Scientific Reports 6: 24515 (Journal)

Registered Authors

Del Giacco, Luca, Ghilardi, Anna, Prosperi, Laura

Keywords

Amyotrophic lateral sclerosis, Cellular neuroscience

MeSH Terms

Action Potentials/drug effects*
Action Potentials/genetics*
Amyotrophic Lateral Sclerosis/diagnosis
Amyotrophic Lateral Sclerosis/genetics*
Animals
Animals, Genetically Modified
Disease Models, Animal
Gene Expression
Locomotion
Motor Activity/drug effects
Motor Neurons/drug effects*
Motor Neurons/physiology*
Muscles/pathology
Mutation
Neuromuscular Junction/metabolism
Phenotype
Phenylglyoxal/analogs & derivatives*
Phenylglyoxal/pharmacology
Riluzole/pharmacology
Spinal Cord/pathology
Superoxide Dismutase/genetics*
Zebrafish

(all 22)

PubMed

27079797 Full text @ Sci. Rep.

Abstract

The pathogenic role of SOD1 mutations in amyotrophic lateral sclerosis (ALS) was investigated using a zebrafish disease model stably expressing the ALS-linked G93R mutation. In addition to the main pathological features of ALS shown by adult fish, we found remarkably precocious alterations in the development of motor nerve circuitry and embryo behavior, and suggest that these alterations are prompted by interneuron and motor neuron hyperexcitability triggered by anomalies in the persistent pacemaker sodium current INaP. The riluzole-induced modulation of INaP reduced spinal neuron excitability, reverted the behavioral phenotypes and improved the deficits in motor nerve circuitry development, thus shedding new light on the use of riluzole in the management of ALS. Our findings provide a valid phenotype-based tool for unbiased in vivo drug screening that can be used to develop new therapies.

Genes / Markers

Marker	Marker Type	Name
chrna1	GENE	cholinergic receptor, nicotinic, alpha 1 (muscle)
elavl3	GENE	ELAV like neuron-specific RNA binding protein 3
sod1	GENE	superoxide dismutase 1, soluble

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Figures

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Expression

Gene	Fish	Conditions	Stage	Anatomy	Assay	Figure
chrna1	os10Tg/+	standard conditions	Long-pec	fast muscle cell postsynapse of neuromuscular junction	OTHR	Fig. 4
chrna1	os10Tg/+	standard conditions	Day 4	fast muscle cell postsynapse of neuromuscular junction	OTHR	Fig. 4
chrna1	os10Tg/+	standard conditions	Adult	fast muscle cell postsynapse of neuromuscular junction	OTHR	Fig. 2
chrna1	os4Tg/+	standard conditions	Day 4	fast muscle cell postsynapse of neuromuscular junction	OTHR	Fig. 4
chrna1	WT	standard conditions	Day 4	fast muscle cell postsynapse of neuromuscular junction	OTHR	Fig. 4
chrna1	WT	standard conditions	Long-pec	fast muscle cell postsynapse of neuromuscular junction	OTHR	Fig. 4
chrna1	WT	standard conditions	Adult	fast muscle cell postsynapse of neuromuscular junction	OTHR	Fig. 2

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Phenotype

Fish	Conditions	Stage	Phenotype	Figure
WT	chemical treatment by environment: Riluzole	20-25 somites	motor neuron membrane depolarization decreased frequency, abnormal	Fig. 8
WT	chemical treatment by environment: Riluzole	20-25 somites	spinal cord interneuron membrane depolarization decreased frequency, abnormal	Fig. 9
WT	chemical treatment by environment: Riluzole	20-25 somites	swimming decreased occurrence, abnormal	Fig. 7
WT	chemical treatment by environment: Riluzole	Prim-5	motor neuron axon branchiness, normal	Fig. 7
WT	chemical treatment by environment: Riluzole	Prim-5	motor neuron axon length, normal	Fig. 7
os10Tg/+	control	20-25 somites	motor neuron membrane depolarization increased frequency, abnormal	Fig. 8
os10Tg/+	control	20-25 somites	spinal cord interneuron membrane depolarization increased frequency, abnormal	Fig. 9
os10Tg/+	control	20-25 somites	swimming increased occurrence, abnormal	Fig. 7
os10Tg/+	control	Prim-5	motor neuron axon decreased length, abnormal	Fig. 7
os10Tg/+	control	Prim-5	motor neuron axon increased branchiness, abnormal	Fig. 7

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Mutations / Transgenics

Allele	Construct	Type	Affected Genomic Region
os4Tg	Tg(sod1:sod1,hsp70l:DsRed)	Transgenic Insertion
os10Tg	Tg(sod1:sod1_G93R,hsp70l:DsRed)	Transgenic Insertion

Human Disease / Model

Human Disease	Fish	Conditions	Evidence
amyotrophic lateral sclerosis	os10Tg/+	standard conditions	TAS

Sequence Targeting Reagents

Fish

Fish
os4Tg/+
os10Tg/+
WT

Antibodies

Orthology

Engineered Foreign Genes

Marker	Marker Type	Name
DsRed	EFG	DsRed

Mapping

Benedetti et al., 2016 ZDB-PUB-160417-10 PMID:27079797

INaP selective inhibition reverts precocious inter- and motorneurons hyperexcitability in the Sod1-G93R zebrafish ALS model

Benedetti et al., 2016

ZDB-PUB-160417-10
PMID:27079797