Elsevier

Progress in Neurobiology

Volume 118, July 2014, Pages 36-58
Progress in Neurobiology

Zebrafish models of human motor neuron diseases: Advantages and limitations

https://doi.org/10.1016/j.pneurobio.2014.03.001Get rights and content
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Highlights

  • Zebrafish offer an excellent alternative vertebrate model for studying motor neuron diseases.

  • It is suitable for exploring the functional effects of human mutations and environmental factors.

  • It represents a good predictive model for identifying chemical suppressors of human diseases.

Abstract

Motor neuron diseases (MNDs) are an etiologically heterogeneous group of disorders of neurodegenerative origin, which result in degeneration of lower (LMNs) and/or upper motor neurons (UMNs). Neurodegenerative MNDs include pure hereditary spastic paraplegia (HSP), which involves specific degeneration of UMNs, leading to progressive spasticity of the lower limbs. In contrast, spinal muscular atrophy (SMA) involves the specific degeneration of LMNs, with symmetrical muscle weakness and atrophy. Amyotrophic lateral sclerosis (ALS), the most common adult-onset MND, is characterized by the degeneration of both UMNs and LMNs, leading to progressive muscle weakness, atrophy, and spasticity. A review of the comparative neuroanatomy of the human and zebrafish motor systems showed that, while the zebrafish was a homologous model for LMN disorders, such as SMA, it was only partially relevant in the case of UMN disorders, due to the absence of corticospinal and rubrospinal tracts in its central nervous system. Even considering the limitation of this model to fully reproduce the human UMN disorders, zebrafish offer an excellent alternative vertebrate model for the molecular and genetic dissection of MND mechanisms. Its advantages include the conservation of genome and physiological processes and applicable in vivo tools, including easy imaging, loss or gain of function methods, behavioral tests to examine changes in motor activity, and the ease of simultaneous chemical/drug testing on large numbers of animals. This facilitates the assessment of the environmental origin of MNDs, alone or in combination with genetic traits and putative modifier genes. Positive hits obtained by phenotype-based small-molecule screening using zebrafish may potentially be effective drugs for treatment of human MNDs.

Abbreviations

AChR
acetylcholine receptor
α-MNs
alpha motor neurons
ALS
amyotrophic lateral sclerosis
AMO
antisense morpholino oligonucleotide
AMPAR
α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors
BMP
bone morphogenetic protein
BVVL
Brown-Vialetto-Van Laere syndrome
CaP MNs
caudal primary motor neurons
CMT
Charcot-Marie-Tooth disease
CMT2
axonal form of Charcot-Marie-Tooth disease
CNS
central nervous systems
CST
corticospinal tract
dHMN
distal hereditary motor neuropathy
dpf
days post fertilization
DCSMA
dominant congenital SMA
EMS
embryonic malabsorption syndrome
ER
endoplasmic reticulum
f-ALS
familial amyotrophic lateral sclerosis
FL
Fazio-Londe syndrome
FUS
fused-in-sarcoma
γ-MNs
gamma motor neurons
hpf
hours post fertilization
HSP
hereditary spastic paraplegia
IN
interneurons
LAAHD
lethal arthrogryposis with anterior horn cell disease
LCCS1
lethal congenital contracture syndrome 1
LCST
lateral corticospinal tract
LMC
lateral motor columns
LMNs
lower motor neurons
MiP MNs
middle primary motor neurons
MLF
medial longitudinal fascicle
MNs
motor neurons
MNDs
motor neuron diseases
MMC
medial motor column
NMJ
neuromuscular junction
NMLF
nucleus of the medial longitudinal fasciculus
PLS
primary lateral sclerosis
PMNs
primary motor neurons
PCH
pontocerebellar hypoplasia
RF
reticular formation
RoP MNs
rostral primary motor neurons
s-ALS
sporadic amyotrophic lateral sclerosis
SBMA
spinal and bulbar muscular atrophy
SuC
superior colliculus
SMA
spinal muscular atrophy
SMA-PME
spinal muscular atrophy with progressive myoclonic epilepsy
SMN1
survival of motor neuron 1
SMN2
survival of motor neuron 2
SMNs
secondary motor neurons
SOD1
soluble cooper/zinc superoxide dismutase 1
TARDBP
TAR DNA-binding protein
UMNs
upper motor neurons
VaP
variable primary motor neurons
VCST
ventral corticospinal tract
VEGF
vascular endothelial growth factor
VN
vestibular nuclei
vS
ventrally projecting secondary motor neurons
WT
wild-type

Keywords

Motor neuron diseases
Zebrafish
Upper and lower motor neurons
Hereditary spastic paraplegia
Amyotrophic lateral sclerosis
Spinal muscular atrophy

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