Impaired PtdIns(4,5)P2 synthesis in nerve terminals produces defects in synaptic vesicle trafficking

Paolo, Gilbert Di; Moskowitz, Howard S.; Gipson, Keith E.; Wenk, Markus R.; Voronov, Sergey V.; Obayashi, Masanori; Flavell, Richard A.; Fitzsimonds, Reiko Maki; Ryan, Timothy A.; Camilli, Pietro De

doi:10.1038/nature02896

Cited by 340 publications

(373 citation statements)

References 48 publications

Supporting

Mentioning

347

Contrasting

Unclassified

Order By: Relevance

“…Whereas PIPK1␥ synthesizes PtdIns(4,5)P 2 , synaptojanin 1 dephosphorylates this lipid at sites of endocytosis and may also help to balance the action of PIPK1␥ at the plasma membrane (1,3,4). Genetic ablation of these enzymes in the mouse leads to early postnatal lethality likely caused by defects in neurotransmission (3,4). The critical importance of synaptojanin 1 at synapses is corroborated by genetic studies in worms, flies, and zebrafish (5)(6)(7).…”

Section: Phosphatidylinositol-45-bisphosphate [Ptdins(45)p2mentioning

confidence: 77%

“…At neuronal synapses, where normal PtdIns(4,5)P 2 balance is required for proper neurotransmission, two brain-enriched enzymes, phosphatidylinositol phosphate kinase type 1␥ (PIPK1␥) and synaptojanin 1, are key factors controlling the levels of this phospholipid (1,3,4). Whereas PIPK1␥ synthesizes PtdIns(4,5)P 2 , synaptojanin 1 dephosphorylates this lipid at sites of endocytosis and may also help to balance the action of PIPK1␥ at the plasma membrane (1,3,4). Genetic ablation of these enzymes in the mouse leads to early postnatal lethality likely caused by defects in neurotransmission (3,4).…”

Section: Phosphatidylinositol-45-bisphosphate [Ptdins(45)p2mentioning

confidence: 99%

See 1 more Smart Citation

Synaptojanin 1-linked phosphoinositide dyshomeostasis and cognitive deficits in mouse models of Down's syndrome

Voronov

Frère²,

Giovedì³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

152

139

View full text Add to dashboard Cite

Phosphatidylinositol-4,5-bisphosphate [PtdIns(4,5)P2] is a signaling phospholipid implicated in a wide variety of cellular functions. At synapses, where normal PtdIns(4,5)P 2 balance is required for proper neurotransmission, the phosphoinositide phosphatase synaptojanin 1 is a key regulator of its metabolism. The underlying gene, SYNJ1, maps to human chromosome 21 and is thus a candidate for involvement in Down's syndrome (DS), a complex disorder resulting from the overexpression of trisomic genes. Here, we show that PtdIns(4,5)P2 metabolism is altered in the brain of Ts65Dn mice, the most commonly used model of DS. This defect is rescued by restoring Synj1 to disomy in Ts65Dn mice and is recapitulated in transgenic mice overexpressing Synj1 from BAC constructs. These transgenic mice also exhibit deficits in performance of the Morris water maze task, suggesting that PtdIns(4,5)P 2 dyshomeostasis caused by gene dosage imbalance for Synj1 may contribute to brain dysfunction and cognitive disabilities in DS.Alzheimer's disease ͉ inositol 5-phosphatase ͉ phosphatidylinositol-4,5-bisphosphate ͉ phosphatidylinositol phosphate kinase ͉ synapse

show abstract

Section: Phosphatidylinositol-45-bisphosphate [Ptdins(45)p2mentioning

confidence: 77%

Section: Phosphatidylinositol-45-bisphosphate [Ptdins(45)p2mentioning

confidence: 99%

Synaptojanin 1-linked phosphoinositide dyshomeostasis and cognitive deficits in mouse models of Down's syndrome

Voronov

Frère²,

Giovedì³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

152

139

View full text Add to dashboard Cite

show abstract

“…In vitro lipid phosphorylation assays on postnuclear supernatant of HEK293, Neuro2a, or CHO cells expressing either WT or FAD mutant PS1 and PS2 were carried out as described in ref. 37.…”

Section: Methodsmentioning

confidence: 99%

“…Thus, to determine more directly whether the presence of presenilin FAD mutations results in aberrant PIP 2 metabolism, we carried out analysis of phosphoinositide turnover by using a cell-free radiolabeling assay in the presence of [␥-32 P]ATP (Fig. 3A) (37). Incorporation of radioactive phosphate into phospholipids occurs through phosphorylation reactions mediated by lipid kinases but also reflects the contribution of phosphatases and phospholipases present in cell extracts.…”

Section: Fad-associated Mutant Presenilinsmentioning

confidence: 99%

Presenilin mutations linked to familial Alzheimer's disease cause an imbalance in phosphatidylinositol 4,5-bisphosphate metabolism

Landman

Jeong

Shin

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

125

121

View full text Add to dashboard Cite

Phosphatidylinositol 4,5-bisphosphate (PIP2) is an important cellular effector whose functions include the regulation of ion channels and membrane trafficking. Aberrant PIP 2 metabolism has also been implicated in a variety of human disease states, e.g., cancer and diabetes. Here we report that familial Alzheimer's disease (FAD)-associated presenilin mutations cause an imbalance in PIP 2 metabolism. We find that the transient receptor potential melastatin 7 (TRPM7)-associated Mg 2؉ -inhibited cation (MIC) channel underlies ion channel dysfunction in presenilin FAD mutant cells, and the observed channel deficits are restored by the addition of PIP 2, a known regulator of the MIC/TRPM7 channel. Lipid analyses show that PIP 2 turnover is selectively affected in FAD mutant presenilin cells. We also find that modulation of cellular PIP 2 closely correlates with 42-residue amyloid ␤-peptide (A␤42) levels. Our data suggest that PIP 2 imbalance may contribute to Alzheimer's disease pathogenesis by affecting multiple cellular pathways, such as the generation of toxic A␤42 as well as the activity of the MIC/TRPM7 channel, which has been linked to other neurodegenerative conditions. Thus, our study suggests that brain-specific modulation of PIP 2 may offer a therapeutic approach in Alzheimer's disease.␤-amyloid precursor protein ͉ channel ͉ secretase ͉ transient receptor potential melastatin 7 (TRPM7) ͉ capacitative calcium entry

show abstract

“…Three major PI5KI isoforms (␣, ␤, and ␥) have been identified. [12][13][14][15] Increasing evidences indicate that PI5KIs, providing spatially and functionally distinct PIP2 pools, guarantee the regulation of specific cellular events: PI5KI␥, for instance, is required for focal adhesion and synaptic vesicle trafficking, 16,17 PI5KI␤ for constitutive receptor endocytosis, 18 whereas PI5KI␣ acts in the regulation of processes dependent on local changes of actin dynamics, such as membrane ruffling and phagocytosis. 19,20 In this report, we took advantage of the fusion protein consisting of GFP and the pleckstrin homology (PH) domain of PLC␦1, that is known to bind PIP2 with high affinity and specificity, [21][22][23] to monitor the dynamics and function of PIP2 during the cytotoxic event.…”

Section: Introductionmentioning

confidence: 99%

PI5KI-dependent signals are critical regulators of the cytolytic secretory pathway

Micucci

Capuano

Marchetti

et al. 2008

Blood

View full text Add to dashboard Cite

Although membrane phospholipid phosphatidylinositol-4,5bisphosphate (PIP2) plays a key role as signaling intermediate and coordinator of actin dynamics and vesicle trafficking, it remains completely unknown its involvement in the activation of cytolytic machinery. By live confocal imaging of primary human natural killer (NK) cells expressing the chimeric protein GFP-PH, we observed, during effector-target cell interaction, the consumption of a preexisting PIP2 pool, which is critically required for the activation of cytolytic machinery. We identified type I phosphatidylinositol-4-phosphate-5-kinase (PI5KI) ␣ and ␥ isoforms as the enzymes responsible for PIP2 synthesis in NK cells. By hRNA-driven gene silencing, we observed that both enzymes are required for the proper activation of NK cytotoxicity and for inositol-1,4,5-trisphosphate (IP3) generation on receptor stimulation. In an attempt to elucidate the specific step controlled by PI5KIs, we found that lytic granule secretion but not polarization resulted in impaired PI5KI␣-and PI5KI␥-silenced cells. Our findings delineate a novel mechanism implicating PI5KI␣ and PI5KI␥ isoforms in the synthesis of PIP2 pools critically required for IP3-dependent Ca 2؉ IntroductionNatural killer (NK) cells and cytotoxic T lymphocytes are critical effectors in the defense against tumor and viral infections 1 ; they exert cytotoxic function through the polarized secretion of granules containing proteolytic molecules, such as perforin and granzymes. This process involves several steps, including the formation of a cytolytic synapse between cytolytic effector and target cell, the rapid reorientation of the microtubule-organizing center along with lytic granules toward the target contact area followed by granule docking and fusion at specialized secretory domains within the cytolytic synapse. 2,3 Several structurally distinct receptors have been implicated in the activation of NK-cell cytolytic machinery: when cross-linked by the corresponding ligands on target cell, they trigger multiple and intersecting signaling pathways responsible for functional activation. 4 A vast array of activating NK receptors belonging to different families are coupled to the lipid modifying enzymes phosphatidylinositol3-kinase (PI3K) and phospholipase C␥ (PLC␥), which provide signals critically required for the activation of the cytolytic machinery [5][6][7][8] ; notably, both enzymes use the membrane phospholipid phosphatidylinositol-4,5-bisphosphate (PIP2) as common substrate. 9 Besides its role as signaling intermediate, PIP2 also acts as critical regulator of various cellular processes, including actin remodeling, membrane and vesicle trafficking, adhesion, and ion transport. 10,11 Surprisingly, the role of PIP2 and its regulatory mechanisms in lymphocyte-mediated cytotoxicity remain completely undefined.The main cellular source of PIP2 are type I phosphatidylinositol-4-phosphate-5-kinase (PI5KI) family members which phosphorylate PI4P on the D5 position of the inositol ring. Three major PI5KI is...

show abstract

Impaired PtdIns(4,5)P2 synthesis in nerve terminals produces defects in synaptic vesicle trafficking

Cited by 340 publications

References 48 publications

Synaptojanin 1-linked phosphoinositide dyshomeostasis and cognitive deficits in mouse models of Down's syndrome

Synaptojanin 1-linked phosphoinositide dyshomeostasis and cognitive deficits in mouse models of Down's syndrome

Presenilin mutations linked to familial Alzheimer's disease cause an imbalance in phosphatidylinositol 4,5-bisphosphate metabolism

PI5KI-dependent signals are critical regulators of the cytolytic secretory pathway

Contact Info

Product

Resources

About