title: 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.
authors.affiliation: Sera Prognostics, Inc., Salt Lake City, Utah, United States of America.
authors.forename: Andrew
authors.initials: A
authors.lastname: Gassman
authors.forename: Le T
authors.initials: le T
authors.lastname: Hao
authors.forename: Leena
authors.initials: L
authors.lastname: Bhoite
authors.forename: Chad L
authors.initials: CL
authors.lastname: Bradford
authors.forename: Chi-Bin
authors.initials: CB
authors.lastname: Chien
authors.forename: Christine E
authors.initials: CE
authors.lastname: Beattie
authors.forename: John P
authors.initials: JP
authors.lastname: Manfredi
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000096:biosynthesis; D000818:Animals; D001369:Axons / Q000187:drug effects* / Q000378:metabolism; D004195:Disease Models, Animal; D004331:Drosophila melanogaster / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D016547:Kinesins / Q000172:deficiency*; D007814:Larva / Q000187:drug effects / Q000378:metabolism; D008124:Locomotion / Q000187:drug effects; D008297:Male; D009046:Motor Neurons / Q000187:drug effects* / Q000378:metabolism; D009134:Muscular Atrophy, Spinal / Q000188:drug therapy / Q000473:pathology* / Q000503:physiopathology; D016501:Neurites / Q000187:drug effects / Q000378:metabolism; D010446:Peptide Fragments / Q000096:biosynthesis; D013116:Spinal Cord / Q000473:pathology; D015027:Zebrafish
chemical_list: D016229:Amyloid beta-Peptides; D007211:Indoles; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D053829:Amyloid Precursor Protein Secretases; D016547:Kinesins
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