Neurosci Lett. 2015 Sep 25;605:18-23.

PIKfyve mediates the motility of late endosomes and lysosomes in neuronal dendrites.

Tsuruta F1, 2, Dolmetsch RE2.

1Graduate School of Life and Environmental Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8577, Japan; Electronic address: tsuruta.fuminori.fn@u.tsukuba.ac.jp.

2Department of Neurobiology, Stanford University School of Medicine, Fairchild Research Laboratories D227, 299 Campus Drive, Stanford, CA 94305, USA.

 

Abstract:

The endosome/lysosome system in the nervous system is critically important for a variety of neuronal functions such as neurite outgrowth, retrograde transport, and synaptic plasticity. In neurons, the endosome/lysosome system is crucial for the activity-dependent internalization of membrane proteins and contributes to the regulation of lipid level on the plasma membrane. Although homeostasis of membrane dynamics plays important roles in the properties of central nervous systems, it has not been elucidated how endosome/lysosome system is regulated. Here, we report that phosphatidylinositol 3-phosphate 5-kinase (PIKfyve) mediates the motility of late endosomes and lysosomes in neuronal dendrites. Endosomes and lysosomes are highly motile in resting neurons, however knockdown of PIKfyve led to a significant reduction in late endosomes and lysosomes motility. We also found that vesicle acidification is crucial for their motility and PIKfyve is associated with this process indirectly. These data suggest that PIKfyve mediates vesicle motility through the regulation of vesicle integrity in neurons.

PIMD: 27215384

 

Supplement: 

Phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P2) plays important roles in various neuronal functions, including membrane trafficking. Previously, we reported a novel function of phosphatidylinositol 3-phosphate 5-kinase (PIKFyve) 1, which recognizes PtdIns(3)P on the endosomes and phosphorylates it at the 5 position to synthesize PtdIns(3,5)P2. In the previous Neuroscience letters journal, we reported that PIKfyve is able to regulate the motility of both endosomes and lysosomes in neuronal dendrites. As an aberrant PtdIns(3,5)P2 metabolism leads to severe neuromuscular disorders 2, understanding the mechanisms that underlie PtdIns(3,5)P2-regulated vesicle motility could provide a possible clue for a treatment of neuromuscular disorders. So far, several excellent reviews describing the mechanisms of how perturbation of PtdIns(3,5)P2 causes these disorders have already been published 3-5. In this summary, we discuss the potential relevance between the regulation of PtdIns(3,5)P2 and psychiatric disorders.

It has been thought that precise regulation of PtdIns(3,5)P2 turnover is essential for life maintenance. Indeed, loss of PIKfyve gene results in early embryonic lethality in mice 6. Furthermore, knockout mice of Fig4 gene, which is a PtdIns(3,5)P2 phosphatase, are also neonatal lethal, demonstrating that precise turnover of PtdIns(3,5)P2 is enormously important. Interestingly, Fig4 may act not only as PtdIns(3,5)P2 phosphatase, but also as activator of PIKfyve. Dysfunctions of Fig4 significantly decreases the amount of PtdIns(3,5)P2 2. These observations prompt us to investigate a phenomenon arise from a perturbation of PtdIns(3,5)P2 turnover using Fig4 mutant mice. While investigating the Fig4 mutant mice, we fortuitously noticed that heterozygous mutant (Fig4+/-) mice were hyperactive and aggressive compared to control mice. To investigate whether Fig4+/- mice, which potently have a low amount of PtdIns(3,5)P2 in brains, exhibit certainly abnormal phenotype, we performed several behavior experiments. In consequence, it seems likely that Fig4+/- mice exhibit psychiatric phenotypes (unpublished data). Intriguingly, Fig4 gene is located on 6q21 region of chromosome associated with schizophrenia and bipolar disorder 7,8. Thus, our preliminary data provide a possibility that perturbation of PtdIns(3,5)P2 causes not only neuromuscular disorders but also psychiatric disorders. Their symptoms could be derived from abnormal membrane trafficking, such as dysregulation of endosome and lysosomal motility in neurons. Therefore, understanding the functions of PtdIns(3,5)P2 might shed light on the novel therapeutic approach for a variety of neuronal diseases, including neuromuscular diseases and psychiatric diseases.

 

References: 

1          Tsuruta, F., Green, E. M., Rousset, M. & Dolmetsch, R. E. PIKfyve regulates CaV1.2 degradation and prevents excitotoxic cell death. J Cell Biol 187, 279-294, doi:10.1083/jcb.200903028 (2009).

2          Chow, C. Y. et al. Mutation of FIG4 causes neurodegeneration in the pale tremor mouse and patients with CMT4J. Nature 448, 68-72 (2007).

3          McCartney, A. J., Zhang, Y. & Weisman, L. S. Phosphatidylinositol 3,5-bisphosphate: low abundance, high significance. Bioessays 36, 52-64, doi:10.1002/bies.201300012 (2014).

4          Shisheva, A. PIKfyve and its Lipid products in health and in sickness. Curr Top Microbiol Immunol 362, 127-162, doi:10.1007/978-94-007-5025-8_7 (2012).

5          Nicot, A. S. & Laporte, J. Endosomal Phosphoinositides and Human Diseases. Traffic (2008).

6          Takasuga, S. et al. Critical roles of type III phosphatidylinositol phosphate kinase in murine embryonic visceral endoderm and adult intestine. Proc Natl Acad Sci U S A 110, 1726-1731, doi:10.1073/pnas.1213212110 (2013).

7          Liang, S. G. & Greenwood, T. A. The impact of clinical heterogeneity in schizophrenia on genomic analyses. Schizophr Res 161, 490-495, doi:10.1016/j.schres.2014.11.019 (2015).

8          Park, N. et al. Linkage analysis of psychosis in bipolar pedigrees suggests novel putative loci for bipolar disorder and shared susceptibility with schizophrenia. Mol Psychiatry 9, 1091-1099, doi:10.1038/sj.mp.4001541 (2004).

 

 

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