title: The Drosophila KIF1A Homolog unc-104 Is Important for Site-Specific Synapse Maturation.
abstract: Mutations in the kinesin-3 family member KIF1A have been associated with hereditary spastic paraplegia (HSP), hereditary and sensory autonomic neuropathy type 2 (HSAN2) and non-syndromic intellectual disability (ID). Both autosomal recessive and autosomal dominant forms of inheritance have been reported. Loss of KIF1A or its homolog unc-104 causes early postnatal or embryonic lethality in mice and Drosophila, respectively. In this study, we use a previously described hypomorphic allele of unc-104, unc-104(bris) , to investigate the impact of partial loss-of-function of kinesin-3 on synapse maturation at the Drosophila neuromuscular junction (NMJ). Unc-104(bris) mutants exhibit structural defects where a subset of synapses at the NMJ lack all investigated active zone (AZ) proteins, suggesting a complete failure in the formation of the cytomatrix at the active zone (CAZ) at these sites. Modulating synaptic Bruchpilot (Brp) levels by ectopic overexpression or RNAi-mediated knockdown suggests that the loss of AZ components such as Ca(2+) channels and Liprin-α is caused by impaired kinesin-3 based transport rather than due to the absence of the key AZ organizer protein, Brp. In addition to defects in CAZ assembly, unc-104(bris) mutants display further defects such as depletion of dense core and synaptic vesicle (SV) markers from the NMJ. Notably, the level of Rab3, which is important for the allocation of AZ proteins to individual release sites, was severely reduced at unc-104(bris) mutant NMJs. Overexpression of Rab3 partially ameliorates synaptic phenotypes of unc-104(bris) larvae, suggesting that lack of presynaptic Rab3 contributes to defects in synapse maturation.
authors.affiliation: Junior Research Group Synaptic Plasticity, Hertie-Institute for Clinical Brain Research, University of TübingenTübingen, Germany; Graudate School of Cellular and Molecular Neuroscience, University of TübingenTübingen, Germany; The Picower Institute for Learning and Memory, Department of Biology and Brain and Cognitive Sciences, Massachusetts Institute of TechnologyCambridge, MA, USA.
authors.forename: Yao V
authors.initials: YV
authors.lastname: Zhang
authors.affiliation: Junior Research Group Synaptic Plasticity, Hertie-Institute for Clinical Brain Research, University of TübingenTübingen, Germany; Graudate School of Cellular and Molecular Neuroscience, University of TübingenTübingen, Germany; Schaller Research Group at the University of Heidelberg and DKFZ, Proteostasis in Neurodegenerative Disease (B180), German Cancer Research CenterHeidelberg, Germany.
authors.forename: Shabab B
authors.initials: SB
authors.lastname: Hannan
authors.affiliation: Schaller Research Group at the University of Heidelberg and DKFZ, Proteostasis in Neurodegenerative Disease (B180), German Cancer Research Center Heidelberg, Germany.
authors.forename: Zeenna A
authors.initials: ZA
authors.lastname: Stapper
authors.affiliation: Junior Research Group Synaptic Plasticity, Hertie-Institute for Clinical Brain Research, University of Tübingen Tübingen, Germany.
authors.forename: Jeannine V
authors.initials: JV
authors.lastname: Kern
authors.affiliation: Schaller Research Group at the University of Heidelberg and DKFZ, Proteostasis in Neurodegenerative Disease (B180), German Cancer Research Center Heidelberg, Germany.
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Jahn
authors.affiliation: Junior Research Group Synaptic Plasticity, Hertie-Institute for Clinical Brain Research, University of TübingenTübingen, Germany; Schaller Research Group at the University of Heidelberg and DKFZ, Proteostasis in Neurodegenerative Disease (B180), German Cancer Research CenterHeidelberg, Germany.
authors.forename: Tobias M
authors.initials: TM
authors.lastname: Rasse
keywords: Drosophila; KIF1A; Rab3; hereditary spastic paraplegia; kinesin-3; neuromuscular junction; synapse maturation; unc-104