Zebrafish models of human motor neuron diseases: Advantages and limitations

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.

Defining the genetic connection linking amyotrophic lateral sclerosis (ALS) with frontotemporal dementia (FTD)

“…These animal models have been evaluated in detail in several recent reviews [131][132][133][134][135]. The mutant SOD1 transgenic mouse model developed in the mid-1990s was a major advance because these transgenic animals exhibit adult-onset clinical signs resembling those seen in ALS patients, including muscle wasting initiated by motor neuron death and paralysis of limbs [136,137].…”

“…Animal models, from yeast to the invertebrates Drosophila and C. elegans, have been used to model the majority of the genetic causes of ALS and FTD [132][133][134]. Similarly, the majority of the ALS and FTD genes have recently been functionally characterized using the vertebrate model zebrafish [131][132][133][134][135][136][137][138][139][140][141][142][143]. These animal models are more efficient than mammalian models at defining the pathogenicity of rare variants found in ALS/ FTD patients, evaluating the degree of interactions among causative genes, and identifying risk factors.…”

Repeated Blood Collection for Blood Tests in Adult Zebrafish

“…In the field of developmental biology, many studies have demonstrated that zebrafish and human show marked similarity in hematopoiesis 3 , hemostasis 4,5 , and myelopoiesis 6 . Adult zebrafish are also used for studying immunological 7 , neurodegenerative 8 and obesityrelated diseases 9 because this model organism shares common pathways with those disrupted in human diseases. For obesity and obesityrelated diseases (diabetes, hepatic steatosis and nonalcoholic steatohepatitis and atherosclerosis), zebrafish blood glucose and lipids levels have been thoroughly investigated in several transgenic and diet-induced obesity models [10][11][12][13] .…”

The combination of limb-bud removal and in ovo electroporation techniques: A new powerful method to study gene function in motoneurons undergoing lesion-induced cell death

“…It is worth of remembering that other non-mammalian animal models have also been integrated to the study of MN degenerative diseases: invertebrates such as the worm (Coenorabditis elegans) (Sleigh et al, 2011;Therrien and Parker, 2014) and the fruit fly (Drosophila melanogaster) (Wang et al, 2011;Cherry et al, 2013) and vertebrates (the zebrafish, Danio rerio) (Babin et al, 2014).…”