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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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Presentation on theme: "Axonal transport, synapse development and mental retardation Yong Q. Zhang Institute of Genetics and Developmental Biology Chinese Academy of Sciences."— Presentation transcript:

1 Axonal transport, synapse development and mental retardation Yong Q. Zhang Institute of Genetics and Developmental Biology Chinese Academy of Sciences

2 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

3 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

4 Chiurazzi et al., EJHG, 2008 Molecular Functions of MR Genes 1 2 3 3 5 ✓

5 Transcriptional/translationalCell-cycle-relatedRos/Rho/PSD95 Nature 2011

6 Neuronal functions of MR-related genes 1, Neurogenesis (microcephaly) 2, Neuronal migration (Lissencephaly) 3, Synapse formation and plasticity

7 Neuronal functions of MR-related genes 1, Neurogenesis (microcephaly) 2, Neuronal migration (Lissencephaly) 3, Synapse formation and plasticity

8 Synapse dysgenesis in MR patients Purpura, Science, 1974 Dendritic spines

9 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)

10 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

11 The role of ACSL4 in neurodevelopment? The mechanism of how the disease develops? ACSL Family ACSL1, 5, 6 ACSL3, 4 { subfamilies no mouse models

12 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)

13 Larval Neuromuscular Junctions NMJ synapses Muscles Large, simple and accessible Griffth and Budnik, 2006 Nerves and NMJ synapses

14 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

15 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

16 SV protein Dynein Active zone t-SNARE Mitochondria Cell adhesion Accumulation of selective axonal cargos

17 Retrograde cargos accumulated in dAcsl mutants MVB: Multiple vesicle body PLB: Prelysosomal body Lb: Lamellated body............

18 Late endosome/ lysosome Autophago- some MVBs Retrograde cargos accumulated in mutants Lysosome+autophagosomeMultiple vesicle body

19 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?

20 Live imaging of axonal transport of GFP-tagged synaptic vesicles Flux Velocity Processivity

21

22 Retrograde transport of synaptic vesicles was impaired in dAcsl mutants

23 Axonal transport of mitochondria was normal in dAcsl mutants

24 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

25 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

26 Accumulation of retrograde cargoes and transport defects ? Defects in synaptic development and function

27 Larval Neuromuscular Junctions NMJ synapses Muscles Large, simple and accessible Griffth and Budnik, 2006 Nerves and NMJ synapses

28 dAcsl mutants show atrophic synaptic terminals Neuronal but not muscular rescue by human ACSL4

29 dAcsl is required for NMJ growth and stability

30 Pre- and post-synaptic components concomitantly reduced in dystrophic NMJs No increased apoptosis Futsch/MAP1Bactive zone proteinPostsynaptic scaffold

31 Will atrophic NMJs show defective transmission? mEJP: miniature EJPs Spontaneous release of single SVs EJP: Excitatory Junction Potentials

32 dAcsl mutations impaired neurotransmission EJP: Excitatory Junction Potentials mEJP: miniature excitatory junction potentials

33 dAcsl mutations impaired neurotransmission Neuronal but not muscular rescue by human ACSL4

34 Axonal jam and retrograde transport defects NMJ synapse atrophy Reduced neurotransmission Can these phenotypes be corrected by induced expression?

35 Drug-induced tissue specific expression Osterwalder et al., PNAS, 2001 Gal4

36 Aggregates were rescued by induced expression Together with NMJ rescue

37 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

38 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

39

40 Acyl-CoA is central to diverse processes

41 K294E Q419R W685@ R570S P375L V594D dACSL-8dACSL-1 mutations in patients Conservation is not restricted


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