Small Molecule Suppressors of Drosophila Kinesin Deficiency Rescue Motor Axon Development in a Zebrafish Model of Spinal Muscular Atrophy

Abstract

Proximal spinal muscular atrophy (SMA) is the most common inherited motor neuropathy and the leading hereditary cause of infant mortality. Currently there is no effective treatment for the disease, reflecting a need for pharmacologic interventions that restore performance of dysfunctional motor neurons or suppress the consequences of their dysfunction. In a series of assays relevant to motor neuron biology, we explored the activities of a collection of tetrahydroindoles that were reported to alter the metabolism of amyloid precursor protein (APP). In Drosophila larvae the compounds suppressed aberrant larval locomotion due to mutations in the Khc and Klc genes, which respectively encode the heavy and light chains of kinesin-1. A representative compound of this class also suppressed the appearance of axonal swellings (alternatively termed axonal spheroids or neuritic beads) in the segmental nerves of the kinesin-deficient Drosophila larvae. Given the importance of kinesin-dependent transport for extension and maintenance of axons and their growth cones, three members of the class were tested for neurotrophic effects on isolated rat spinal motor neurons. Each compound stimulated neurite outgrowth. In addition, consistent with SMA being an axonopathy of motor neurons, the three axonotrophic compounds rescued motor axon development in a zebrafish model of SMA. The results introduce a collection of small molecules as pharmacologic suppressors of SMA-associated phenotypes and nominate specific members of the collection for development as candidate SMA therapeutics. More generally, the results reinforce the perception of SMA as an axonopathy and suggest novel approaches to treating the disease.

Fishing for causes and cures of motor neuron disorders

“…Pharmacological or genetic suppression of ubiquitin-like modifier activating enzyme 1 (UBA1) was sufficient to recapitulate an SMA-like neuromuscular pathology in zebrafish, suggesting that UBA1 directly has an important role in disease pathogenesis. Tetrahydroindoles that alter the processing of amyloid precursor protein were tested in these various models and revealed that three of these compounds rescued motor neuron defects in smn morpholino knockdown zebrafish ( Gassman et al, 2013 ). More generally, the results suggest that SMA could be an axonopathy (a disease in which the normal function of axons is disrupted), suggesting novel strategies for treating the disease.…”

Axonal transport and neurodegenerative disease: vesicle-motor complex formation and their regulation

“…238 Interestingly, pharmacological compounds known to rescue kinesin-mediated larval locomotion in Drosophila stimulated neurite growth in rat spinal neurons and rescued motor neuron development in a Zebra fish model of SMA. 239 Taken together, these observations suggest that SMN has a role in axonal transport and may form the unique cargo complex that interacts with MT motors.…”

Modeling Spinal Muscular Atrophy in Zebrafish: Current Advances and Future Perspectives

“…A study by Gassman et al found that small molecules known for suppressing Kinesin in Drosophila (SBL-154, SBL-185, and SBL-190) can rescue motor axon abnormalities from transgenic Smn-deficient and MO-injected zebrafish SMA models. However, the authors did not find an increase in the lifespan of transgenic Smn-deficient zebrafish lines when embryos were treated with SBL-154, suggesting that the effect of this compound could be restricted to motor neurons [43].…”