Fishing for causes and cures of motor neuron disorders

Abstract

Motor neuron disorders (MNDs) are a clinically heterogeneous group of neurological diseases characterized by progressive degeneration of motor neurons, and share some common pathological pathways. Despite remarkable advances in our understanding of these diseases, no curative treatment for MNDs exists. To better understand the pathogenesis of MNDs and to help develop new treatments, the establishment of animal models that can be studied efficiently and thoroughly is paramount. The zebrafish (Danio rerio) is increasingly becoming a valuable model for studying human diseases and in screening for potential therapeutics. In this Review, we highlight recent progress in using zebrafish to study the pathology of the most common MNDs: spinal muscular atrophy (SMA), amyotrophic lateral sclerosis (ALS) and hereditary spastic paraplegia (HSP). These studies indicate the power of zebrafish as a model to study the consequences of disease-related genes, because zebrafish homologues of human genes have conserved functions with respect to the aetiology of MNDs. Zebrafish also complement other animal models for the study of pathological mechanisms of MNDs and are particularly advantageous for the screening of compounds with therapeutic potential. We present an overview of their potential usefulness in MND drug discovery, which is just beginning and holds much promise for future therapeutic development.

Keywords: ALS; Drug discovery; HSP; Motor neuron disorders; SMA; Zebrafish.

Fig. 1.

Common pathological pathways in ALS, SMA and HSP. An illustration of a motor neuron, highlighting common possible mechanisms in the literature linking the MNDs. A non-exhaustive list of genes involved is given for each disease.

Fig. 2.

Motor neuron disorders: from bench to clinic. One proposed strategy for drug discovery for MNDs (and other diseases) is to first start a large and rapid chemical screen in C. elegans and confirm the positive hits in a zebrafish. Once positive compounds that reverse or ameliorate the disease phenotype in both models are encountered, they can then be tested in mammal systems and/or go straight to clinical trials, if the compounds are already approved for safety and efficacy by the FDA.