Zhang, Y. et al. Loss of Vac14, a regulator of the signaling lipid phosphatidylinositol 3,5-bisphosphate, results in neurodegeneration in mice. Proc. Natl Acad. Sci. USA 104, 17518-17523

Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109-2216, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 11/2007; 104(44):17518-23. DOI: 10.1073/pnas.0702275104
Source: PubMed


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 · 3.45 Impact Factor
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    • "The phosphoinositide PI(3,5)P2 is enriched on late endosome/lysosome membranes. Mice with genetic mutations affecting the phosphatases and kinases involved in regulation of PI(3,5)P2 have neurological defects, cells with large vacuoles, abnormal endolysosomal membranes [63]–[66], and defective autophagy [67]. Similarly, PI3P is enriched on autophagosome membranes and deletion or mutation of PI3P modulating enzymes result in aberrant autophagy [68]. "
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    ABSTRACT: Highly polarized cells such as photoreceptors require precise and efficient strategies for establishing and maintaining the proper subcellular distribution of proteins. The signals and molecular machinery that regulate trafficking and sorting of synaptic proteins within cone inner segments is mostly unknown. In this study, we show that the polyphosphoinositide phosphatase Synaptojanin 1 (SynJ1) is critical for this process. We used transgenic markers for trafficking pathways, electron microscopy, and immunocytochemistry to characterize trafficking defects in cones of the zebrafish mutant, nrc(a14) , which is deficient in phosphoinositide phosphatase, SynJ1. The outer segments and connecting cilia of nrc(a14) cone photoreceptors are normal, but RibeyeB and VAMP2/synaptobrevin, which normally localize to the synapse, accumulate in the nrc(a14) inner segment. The structure of the Endoplasmic Reticulum in nrc(a14) mutant cones is normal. Golgi develop normally, but later become disordered. Large vesicular structures accumulate within nrc(a14) cone photoreceptor inner segments, particularly after prolonged incubation in darkness. Cone inner segments of nrc (a14) mutants also have enlarged acidic vesicles, abnormal late endosomes, and a disruption in autophagy. This last pathway also appears exacerbated by darkness. Taken altogether, these findings show that SynJ1 is required in cones for normal endolysosomal trafficking of synaptic proteins.
    PLoS ONE 01/2014; 9(1):e84394. DOI:10.1371/journal.pone.0084394 · 3.23 Impact Factor
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    • "Furthermore, mutant mice with absent Vac14, a gene coding for an FIG 4 interactor, also shows neurodegeneration. Mutations in the two components of the PI(3,5)P2 regulatory complex, FIG 4 and Vac14, lead to cytoplasmic inclusion body formation containing p62, LC3-II and LAMP-2 in the brain, suggesting that autophagy may play a role in the gene mutations induced neurodegeneration [57]. "
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    ABSTRACT: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder involving both upper motor neurons (UMN) and lower motor neurons (LMN). Enormous research has been done in the past few decades in unveiling the genetics of ALS, successfully identifying at least fifteen candidate genes associated with familial and sporadic ALS. Numerous studies attempting to define the pathogenesis of ALS have identified several plausible determinants and molecular pathways leading to motor neuron degeneration, which include oxidative stress, glutamate excitotoxicity, apoptosis, abnormal neurofilament function, protein misfolding and subsequent aggregation, impairment of RNA processing, defects in axonal transport, changes in endosomal trafficking, increased inflammation, and mitochondrial dysfunction. This review is to update the recent discoveries in genetics of ALS, which may provide insight information to help us better understanding of the devastating disease.
    Molecular Neurodegeneration 08/2013; 8(1):28. DOI:10.1186/1750-1326-8-28 · 6.56 Impact Factor
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