Loss of Vac14, a regulator of the signaling lipid phosphatidylinositol 3,5-bisphosphate, results in neurodegeneration in mice

Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109-2216, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.81). 11/2007; 104(44):17518-23. DOI: 10.1073/pnas.0702275104
Source: PubMed

ABSTRACT The signaling lipid, phosphatidylinositol 3,5-bisphosphate (PI(3,5)P(2)), likely functions in multiple signaling pathways. Here, we report the characterization of a mouse mutant lacking Vac14, a regulator of PI(3,5)P(2) synthesis. The mutant mice exhibit massive neurodegeneration, particularly in the midbrain and in peripheral sensory neurons. Cell bodies of affected neurons are vacuolated, and apparently empty spaces are present in areas where neurons should be present. Similar vacuoles are found in cultured neurons and fibroblasts. Selective membrane trafficking pathways, especially endosome-to-TGN retrograde trafficking, are defective. This report, along with a recent report on a mouse with a null mutation in Fig4, presents the unexpected finding that the housekeeping lipid, PI(3,5)P(2), is critical for the survival of neural cells.

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    • "Experimental work by Katoh et al. (2009) indicates that clavesins specifically function in neurons in a transport pathway between early endosomes and mature lysosomes and that one of the molecules they bind is phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P 2 ). Mutations in mice that deplete PtdIns(3,5)P 2 produce neurodegeneration phenotypes with little effect on other tissues (Zhang et al., 2007). "
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    ABSTRACT: CRAL_TRIO domain proteins are known to bind small lipophilic molecules such as retinal, inositol and Vitamin E and include such gene family members as PINTA, α-tocopherol transfer (ATT) proteins, retinoid binding proteins, and clavesins. In insects, very little is known about either the molecular evolution of this family of proteins or their ligand specificity. Here we characterize insect CRAL_TRIO domain proteins and present the first insect CRAL_TRIO protein phylogeny constructed by performing reciprocal BLAST searches of the reference genomes of Drosophila melanogaster, Anopheles gambiae, Apis mellifera, Tribolium castaneum, Bombyx mori, Manduca sexta and Danaus plexippus. We find several highly conserved amino acid residues in the CRAL_TRIO domain-containing genes across insects, and a gene expansion resulting in more than twice as many gene family members in lepidopterans than other surveyed insect species, but no lepidopteran homolog of the PINTA gene in Drosophila. In addition, we examined the expression pattern of CRAL_TRIO domain genes in M. sexta heads using RNA-Seq data. Of the 42 gene family members found in the M. sexta reference genome, we found 30 expressed in the head tissue with similar expression profiles between males and females. Our results suggest this gene family underwent a large expansion in Lepidoptera, making the leptidopteran CRAL_TRIO domain family distinct from other holometabolous insect lineages.
    Insect Biochemistry and Molecular Biology 02/2015; 62. DOI:10.1016/j.ibmb.2015.02.003 · 3.42 Impact Factor
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    • "PIKfyve exists in a complex with the scaffold protein Vac14 and the phosphoinositide 5-phosphatase Fig4, and is the only enzyme found in mammalian cells to produce PI(3,5)P 2 (Duex et al. 2006b; Zhang et al. 2007). Knockout of PIKfyve in mice results in embryonic lethality (Ikonomov et al. 2011), and knockout of Vac14 or Fig4, which results in a roughly 50% decrease in total PI(3,5)P 2 levels, leads to severely enlarged vacuoles of late-endocytic origin (Chow et al. 2007; Zhang et al. 2007). It is still unclear how PI(3,5)P 2 regulates late endocytic trafficking, however. "
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    ABSTRACT: Endosomal and lysosomal membrane trafficking requires the coordination of multiple signaling events to control cargo sorting and processing, and endosome maturation. The initiation and termination of signaling events in endosomes and lysosomes is not well understood, but several key regulators have been identified, which include small GTPases, phosphoinositides, and Ca(2+). Small GTPases act as master regulators and molecular switches in a GTP-dependent manner, initiating signaling cascades to regulate the direction and specificity of endosomal trafficking. Phosphoinositides are membrane-bound lipids that indicate vesicular identities for recruiting specific cytoplasmic proteins to endosomal membranes, thus allowing specificity of membrane fusion, fission, and cargo sorting to occur within and between specific vesicle compartments. In addition, phosphoinositides regulate the function of membrane proteins such as ion channels and transporters in a compartment-specific manner to mediate transport and signaling. Finally, Ca(2+). , a locally-acting second messenger released from intracellular ion channels, may provide precise spatiotemporal regulation of endosomal signaling and trafficking events. Small GTPase signaling can regulate phosphoinositide conversion during endosome maturation, and electrophysiological studies on isolated endosomes have shown that endosomal and lysosomal Ca(2+). channels are directly modulated by endosomal lipids. Thus trafficking and maturation of endosomes and lysosomes can be precisely regulated by dynamic changes in GTPases and membrane lipids, as well as Ca(2+). signaling. Importantly, impaired phosphoinositide and Ca(2+). signaling can cause endosomal and lysosomal trafficking defects at the cellular level, and a spectrum of Lysosome Storage Diseases (LSDs).
    The Journal of Physiology 07/2013; 591(18). DOI:10.1113/jphysiol.2013.258301 · 4.54 Impact Factor
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    • "J Biol Chem 277(8):6073–6079. 21. Zhang Y, et al. (2007) Loss of Vac14, a regulator of the signaling lipid phosphatidylinositol 3,5-bisphosphate, results in neurodegeneration in mice. Proc Natl Acad Sci USA 104(44):17518–17523. 22. de Lartigue J, et al. (2009) PIKfyve regulation of endosome-linked pathways. "
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    ABSTRACT: Mutations that cause defects in levels of the signaling lipid phosphatidylinositol 3,5-bisphosphate [PI(3,5)P(2)] lead to profound neurodegeneration in mice. Moreover, mutations in human FIG4 predicted to lower PI(3,5)P(2) levels underlie Charcot-Marie-Tooth type 4J neuropathy and are present in selected cases of amyotrophic lateral sclerosis. In yeast and mammals, PI(3,5)P(2) is generated by a protein complex that includes the lipid kinase Fab1/Pikfyve, the scaffolding protein Vac14, and the lipid phosphatase Fig4. Fibroblasts cultured from Vac14(-/-) and Fig4(-/-) mouse mutants have a 50% reduction in the levels of PI(3,5)P(2), suggesting that there may be PIKfyve-independent pathways that generate this lipid. Here, we characterize a Pikfyve gene-trap mouse (Pikfyve(β-geo/β-geo)), a hypomorph with ∼10% of the normal level of Pikfyve protein. shRNA silencing of the residual Pikfyve transcript in fibroblasts demonstrated that Pikfyve is required to generate all of the PI(3,5)P(2) pool. Surprisingly, Pikfyve also is responsible for nearly all of the phosphatidylinositol-5-phosphate (PI5P) pool. We show that PI5P is generated directly from PI(3,5)P(2), likely via 3'-phosphatase activity. Analysis of tissues from the Pikfyve(β-geo/β-geo) mouse mutants reveals that Pikfyve is critical in neural tissues, heart, lung, kidney, thymus, and spleen. Thus, PI(3,5)P(2) and PI5P have major roles in multiple organs. Understanding the regulation of these lipids may provide insights into therapies for multiple diseases.
    Proceedings of the National Academy of Sciences 10/2012; 109(43):17472-7. DOI:10.1073/pnas.1203106109 · 9.81 Impact Factor
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