Essential role of phosphoinositide metabolism in synaptic vesicle recycling

Ottavio Cremona; Gilbert Di Paolo; Markus R. Wenk; Anita Lüthi; Warren T. Kim; Kohji Takei; Laurie Daniell; Yasuo Nemoto; Stephen B. Shears; Richard A. Flavell; David A. McCormick; Pietro De Camilli

doi:10.1016/S0092-8674(00)81649-9

Essential role of phosphoinositide metabolism in synaptic vesicle recycling

Ottavio Cremona, Gilbert Di Paolo, Markus R. Wenk, Anita Lüthi, Warren T. Kim, Kohji Takei, Laurie Daniell, Yasuo Nemoto, Stephen B. Shears, Richard A. Flavell, David A. McCormick, Pietro De Camilli

Research output: Contribution to journal › Article › peer-review

646 Citations (Scopus)

Abstract

Growing evidence suggests that phosphoinositides play an important role in membrane traffic. A poly-phosphoinositide phosphatase, synaptojanin 1, was identified as a major presynaptic protein associated with endocytic coated intermediates. We report here that synaptojanin 1-deficient mice exhibit neurological defects and die shortly after birth. In neurons of mutant animals, PI(4,5)P₂ levels are increased, and clathrin-coated vesicles accumulate in the cytomatrix-rich area that surrounds the synaptic vesicle cluster in nerve endings. In cell-free assays, reduced phosphoinositide phosphatase activity correlated with increased association of clathrin coats with liposomes. Intracellular recording in hippocampal slices revealed enhanced synaptic depression during prolonged high-frequency stimulation followed by delayed recovery. These results provide genetic evidence for a crucial role of phosphoinositide metabolism in synaptic vesicle recycling.

Original language	English
Pages (from-to)	179-188
Number of pages	10
Journal	Cell
Volume	99
Issue number	2
DOIs	https://doi.org/10.1016/S0092-8674(00)81649-9
Publication status	Published - 1999
Externally published	Yes

ASJC Scopus subject areas

Biochemistry, Genetics and Molecular Biology(all)

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10.1016/S0092-8674(00)81649-9

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@article{713a582533e34d6c88958400f2a01c3c,

title = "Essential role of phosphoinositide metabolism in synaptic vesicle recycling",

abstract = "Growing evidence suggests that phosphoinositides play an important role in membrane traffic. A poly-phosphoinositide phosphatase, synaptojanin 1, was identified as a major presynaptic protein associated with endocytic coated intermediates. We report here that synaptojanin 1-deficient mice exhibit neurological defects and die shortly after birth. In neurons of mutant animals, PI(4,5)P2 levels are increased, and clathrin-coated vesicles accumulate in the cytomatrix-rich area that surrounds the synaptic vesicle cluster in nerve endings. In cell-free assays, reduced phosphoinositide phosphatase activity correlated with increased association of clathrin coats with liposomes. Intracellular recording in hippocampal slices revealed enhanced synaptic depression during prolonged high-frequency stimulation followed by delayed recovery. These results provide genetic evidence for a crucial role of phosphoinositide metabolism in synaptic vesicle recycling.",

author = "Ottavio Cremona and {Di Paolo}, Gilbert and Wenk, {Markus R.} and Anita L{\"u}thi and Kim, {Warren T.} and Kohji Takei and Laurie Daniell and Yasuo Nemoto and Shears, {Stephen B.} and Flavell, {Richard A.} and McCormick, {David A.} and {De Camilli}, Pietro",

note = "Funding Information: We thank Anna Zhang for technical help; Khashayar Farsad for help in electron microscopy experiments; David Brownstein for pathological analysis of mutant mice; Wufan Tao, Di Yang, and Tian Xu for advice in gene targeting; Reinhard Jahn (Gottingen, Germany) for the kind gift of antibodies; and Ezio Perucco and Giuseppe Migliaretti for help in the statistical analysis. This work was supported in part by National Institutes of Health grants to P. D. C. (NS36251 and CA46128) and to D. A. M. (NS26143), by Telethon (project D.61) and MURST (ex-40%) grants to O. C., a Human Frontier Science Program long-term fellowship to O. C. (1996–1997), an EMBO long-term fellowship to G. D. P., a Swiss National Science Foundation grant and a Novartis Stiftung grant to M. W., and a fellowship from the American Epilepsy Foundation to A. L.",

year = "1999",

doi = "10.1016/S0092-8674(00)81649-9",

language = "English",

volume = "99",

pages = "179--188",

journal = "Cell",

issn = "0092-8674",

publisher = "Cell Press",

number = "2",

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TY - JOUR

T1 - Essential role of phosphoinositide metabolism in synaptic vesicle recycling

AU - Cremona, Ottavio

AU - Di Paolo, Gilbert

AU - Wenk, Markus R.

AU - Lüthi, Anita

AU - Kim, Warren T.

AU - Takei, Kohji

AU - Daniell, Laurie

AU - Nemoto, Yasuo

AU - Shears, Stephen B.

AU - Flavell, Richard A.

AU - McCormick, David A.

AU - De Camilli, Pietro

N1 - Funding Information: We thank Anna Zhang for technical help; Khashayar Farsad for help in electron microscopy experiments; David Brownstein for pathological analysis of mutant mice; Wufan Tao, Di Yang, and Tian Xu for advice in gene targeting; Reinhard Jahn (Gottingen, Germany) for the kind gift of antibodies; and Ezio Perucco and Giuseppe Migliaretti for help in the statistical analysis. This work was supported in part by National Institutes of Health grants to P. D. C. (NS36251 and CA46128) and to D. A. M. (NS26143), by Telethon (project D.61) and MURST (ex-40%) grants to O. C., a Human Frontier Science Program long-term fellowship to O. C. (1996–1997), an EMBO long-term fellowship to G. D. P., a Swiss National Science Foundation grant and a Novartis Stiftung grant to M. W., and a fellowship from the American Epilepsy Foundation to A. L.

PY - 1999

Y1 - 1999

N2 - Growing evidence suggests that phosphoinositides play an important role in membrane traffic. A poly-phosphoinositide phosphatase, synaptojanin 1, was identified as a major presynaptic protein associated with endocytic coated intermediates. We report here that synaptojanin 1-deficient mice exhibit neurological defects and die shortly after birth. In neurons of mutant animals, PI(4,5)P2 levels are increased, and clathrin-coated vesicles accumulate in the cytomatrix-rich area that surrounds the synaptic vesicle cluster in nerve endings. In cell-free assays, reduced phosphoinositide phosphatase activity correlated with increased association of clathrin coats with liposomes. Intracellular recording in hippocampal slices revealed enhanced synaptic depression during prolonged high-frequency stimulation followed by delayed recovery. These results provide genetic evidence for a crucial role of phosphoinositide metabolism in synaptic vesicle recycling.

AB - Growing evidence suggests that phosphoinositides play an important role in membrane traffic. A poly-phosphoinositide phosphatase, synaptojanin 1, was identified as a major presynaptic protein associated with endocytic coated intermediates. We report here that synaptojanin 1-deficient mice exhibit neurological defects and die shortly after birth. In neurons of mutant animals, PI(4,5)P2 levels are increased, and clathrin-coated vesicles accumulate in the cytomatrix-rich area that surrounds the synaptic vesicle cluster in nerve endings. In cell-free assays, reduced phosphoinositide phosphatase activity correlated with increased association of clathrin coats with liposomes. Intracellular recording in hippocampal slices revealed enhanced synaptic depression during prolonged high-frequency stimulation followed by delayed recovery. These results provide genetic evidence for a crucial role of phosphoinositide metabolism in synaptic vesicle recycling.

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JO - Cell

JF - Cell

SN - 0092-8674

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ER -

Essential role of phosphoinositide metabolism in synaptic vesicle recycling

Abstract

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