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Axonal transport, synapse development and mental retardation Yong Q. Zhang Institute of Genetics and Developmental Biology Chinese Academy of Sciences
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Mental retardation (Intellectual Disability, Cognitive Disorder) a generalized disorder, characterized by significantly impaired cognitive functioning and deficits in two or more adaptive behaviors with onset before the age of 18. 1-3% of general population is mentally retarded from wikipedia.com
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82 MR genes on the X-chrom. Chiurazzi et al., EJHG, 2008 Syndromic MR: black Non-syndromic MR: *grey MR with neuromuscular defects: +grey CUL4B
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Chiurazzi et al., EJHG, 2008 Molecular Functions of MR Genes 1 2 3 3 5 ✓
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Transcriptional/translationalCell-cycle-relatedRos/Rho/PSD95 Nature 2011
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Neuronal functions of MR-related genes 1, Neurogenesis (microcephaly) 2, Neuronal migration (Lissencephaly) 3, Synapse formation and plasticity
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Neuronal functions of MR-related genes 1, Neurogenesis (microcephaly) 2, Neuronal migration (Lissencephaly) 3, Synapse formation and plasticity
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Synapse dysgenesis in MR patients Purpura, Science, 1974 Dendritic spines
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Mutations in ACSL4 are associated with non-syndromic X-linked mental retardation Meloni et al., Nat Genet, 2002 Longo et al., J Med Genet, 2003 aa Splicing mutant resulting in truncation ACSL: Acyl-CoA Synthetase Long-chain (C12-20)
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ACSL in Lipid Synthesis and ATP Production Fatty acid Acyl-CoA Coenzyme A Glycerol-3-P Diacylglycerol (DAG) Triacylglycerol (TAG) PC, PE, PS Lipid droplet Membrane Components Fatty acid Acyl-CoA Coenzyme A β-oxidation ATP ACSL Endoplasmic ReticulumMitochondria Lipid biosynthesisFatty acid degradation Phosphatidic acid (PA) Coleman et al., Annu Rev Nutri, 2000
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The role of ACSL4 in neurodevelopment? The mechanism of how the disease develops? ACSL Family ACSL1, 5, 6 ACSL3, 4 { subfamilies no mouse models
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50% identity and 67% similarity Zhaohui Wang and colleagues, Hum Mol Genet, 2009 ACSL Family: 1, 3, 4, 5, and 6 ACSL1, 5, 6 ACSL3, 4 (fly dAcsl)
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Larval Neuromuscular Junctions NMJ synapses Muscles Large, simple and accessible Griffth and Budnik, 2006 Nerves and NMJ synapses
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Axonal accumulation of synaptic vesicle protein CSP in dAcsl mutants Wild type dAcsl Ubi. rescue Khc, Dhc WT Hurd and Saxton, Genetics, 1996 Martin et al, Mol Cell Biol, 1999
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A Control B1 dAcsl KO/05847 B2 OK6>Syt-eGFP ChAT B3 B2’ B3' B1’ A’ OK6>Syt-eGFP ChAT merge 20 μm Distally-Biased Axonal Aggregates of SVs ChAT: choline acetyltransferase Motor Neu Sens. Neu AnteriorPosterior Sensory Neuron Motor Neuron
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SV protein Dynein Active zone t-SNARE Mitochondria Cell adhesion Accumulation of selective axonal cargos
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Retrograde cargos accumulated in dAcsl mutants MVB: Multiple vesicle body PLB: Prelysosomal body Lb: Lamellated body............
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Late endosome/ lysosome Autophago- some MVBs Retrograde cargos accumulated in mutants Lysosome+autophagosomeMultiple vesicle body
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dAcsl mutations lead to specific accumulation of retrograde cargoes Synaptic vesicles Autophagosome Lysosome Immunostaining and EM analysis Why did the axonal aggregates of retrograde cargos form in dAcsl mutants?
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Live imaging of axonal transport of GFP-tagged synaptic vesicles Flux Velocity Processivity
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Retrograde transport of synaptic vesicles was impaired in dAcsl mutants
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Axonal transport of mitochondria was normal in dAcsl mutants
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FR WT dfmr1 NOE WT dfmr1 NOE Time percentage * ** * * AT RT Stop RR E 10 m C A B time AnterogradeRetrograde 50 s C,C, A,A, B, AT RT *** Flux (mito. number/min) * * WT dfmr1 NOE D WTdfmr1dfmr1 overexpres. Yao et al., Hum Mol Genet, 2011 dfmr1 regulates axonal transport of mitochondria
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Role of axonal transport in neurodegenerative diseases De Vos et al., Annu Rev Neurosci, 2008 Axonal transport and neurodegenerative disease Chevalier-Larsen and Holzbaur Biochim Biophys Acta, 2006 SV transport defects in dAcsl mutants Mitochondria transport defects in dfmr1 mutants
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Accumulation of retrograde cargoes and transport defects ? Defects in synaptic development and function
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Larval Neuromuscular Junctions NMJ synapses Muscles Large, simple and accessible Griffth and Budnik, 2006 Nerves and NMJ synapses
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dAcsl mutants show atrophic synaptic terminals Neuronal but not muscular rescue by human ACSL4
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dAcsl is required for NMJ growth and stability
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Pre- and post-synaptic components concomitantly reduced in dystrophic NMJs No increased apoptosis Futsch/MAP1Bactive zone proteinPostsynaptic scaffold
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Will atrophic NMJs show defective transmission? mEJP: miniature EJPs Spontaneous release of single SVs EJP: Excitatory Junction Potentials
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dAcsl mutations impaired neurotransmission EJP: Excitatory Junction Potentials mEJP: miniature excitatory junction potentials
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dAcsl mutations impaired neurotransmission Neuronal but not muscular rescue by human ACSL4
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Axonal jam and retrograde transport defects NMJ synapse atrophy Reduced neurotransmission Can these phenotypes be corrected by induced expression?
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Drug-induced tissue specific expression Osterwalder et al., PNAS, 2001 Gal4
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Aggregates were rescued by induced expression Together with NMJ rescue
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dAcsl mutants show distally-biased axonal aggregates and impaired retrograde transport of synaptic vesicles dAcsl is required for synaptic growth, stability and neurotransmission Summary Liu et al., J Neurosci., 2011 SV
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Acknowledgments Zhihua Liu, PhD Yan Huang Zhaohui Wang (PI ) Yi Zhang (mutants & Ab) Di Chen (mutants) Zhihua Liu Yan Huang Grants: National Science Foundation of China Chinese Academy of Sciences The Ministry of Science and Technology
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Acyl-CoA is central to diverse processes
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K294E Q419R W685@ R570S P375L V594D dACSL-8dACSL-1 mutations in patients Conservation is not restricted
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