@article{e216427a161845d58e6390a5a0b28793,
title = "VAMP associated proteins are required for autophagic and lysosomal degradation by promoting a PtdIns4P-mediated endosomal pathway",
abstract = "Mutations in the ER-associated VAPB/ALS8 protein cause amyotrophic lateral sclerosis and spinal muscular atrophy. Previous studies have argued that ER stress may underlie the demise of neurons. We find that loss of VAP proteins (VAPs) leads to an accumulation of aberrant lysosomes and impairs lysosomal degradation. VAPs mediate ER to Golgi tethering and their loss may affect phosphatidylinositol-4-phosphate (PtdIns4P) transfer between these organelles. We found that loss of VAPs elevates PtdIns4P levels in the Golgi, leading to an expansion of the endosomal pool derived from the Golgi. Fusion of these endosomes with lysosomes leads to an increase in lysosomes with aberrant acidity, contents, and shape. Importantly, reducing PtdIns4P levels with a PtdIns4-kinase (PtdIns4K) inhibitor, or removing a single copy of Rab7, suppress macroautophagic/autophagic degradation defects as well as behavioral defects observed in Drosophila Vap33 mutant larvae. We propose that a failure to tether the ER to the Golgi when VAPs are lost leads to an increase in Golgi PtdIns4P levels, and an expansion of endosomes resulting in an accumulation of dysfunctional lysosomes and a failure in proper autophagic lysosomal degradation. Abbreviations: ALS: amyotrophic lateral sclerosis; CSF: cerebrospinal fluid; CERT: ceramide transfer protein; FFAT: two phenylalanines in an acidic tract; MSP: major sperm proteins; OSBP: oxysterol binding protein; PH: pleckstrin homology; PtdIns4P: phosphatidylinositol-4-phosphate; PtdIns4K: phosphatidylinositol 4-kinase; UPR: unfolded protein response; VAMP: vesicle-associated membrane protein; VAPA/B: mammalian VAPA and VAPB proteins; VAPs: VAMP-associated proteins (referring to Drosophila Vap33, and human VAPA and VAPB).",
keywords = "ALS8, PI4KB, VAPA/VAPB, Vap33, autophagy",
author = "Dongxue Mao and Guang Lin and Burak Tepe and Zhongyuan Zuo and Tan, {Kai Li} and Mumine Senturk and Sheng Zhang and Arenkiel, {Benjamin R.} and Marco Sardiello and Bellen, {Hugo J.}",
note = "Funding Information: We thank the BDSC (NIH P40OD018537) for Drosophila stocks. We thank Alberto Di Ronza and Rituraj Pal for providing valuable advice and technical support for the TFEB experiments in mammalian cells. We thank Robin Hiesinger for providing Drosophila Rab7 knockout flies. We thank Linda Partridge for providing Drosophila ATG8a antibody. We thank Hui Ye for providing antibodies and other reagent for Drosophila lysosome and endosome experiments. We thank Berrak Ugur, Karen Schulze and Kartik Venkatachalam for helpful discussions and comments. H.J.B. is an investigator of the Howard Hughes Medical Institute. Confocal microscopy was supported by the Neurovisualization Core of the BCM IDDRC, funded by NICHD U54HD083092. This work was supported by Target ALS, the Robert A. and Renee E. Belfer Family Foundation and the Huffington Foundation to H.J.B; NIH grant R01NS079618 to M. Sardiello and NIH grant R01NS069880 to S.Z. Funding Information: This work was supported by the Howard Hughes Medical Institute; National Institute of Child Health and Human Development [U54HD083092]; National Institutes of Health [R01NS079618]; National Institutes of Health [R01NS069880]; Huffington Foundation; Robert A. and Renee E. Belfer Family Foundation; Target ALS. We thank the BDSC (NIH P40OD018537) for Drosophila stocks. We thank Alberto Di Ronza and Rituraj Pal for providing valuable advice and technical support for the TFEB experiments in mammalian cells. We thank Robin Hiesinger for providing Drosophila Rab7 knockout flies. We thank Linda Partridge for providing Drosophila ATG8a antibody. We thank Hui Ye for providing antibodies and other reagent for Drosophila lysosome and endosome experiments. We thank Berrak Ugur, Karen Schulze and Kartik Venkatachalam for helpful discussions and comments. H.J.B. is an investigator of the Howard Hughes Medical Institute. Confocal microscopy was supported by the Neurovisualization Core of the BCM IDDRC, funded by NICHD U54HD083092. This work was supported by Target ALS, the Robert A. and Renee E. Belfer Family Foundation and the Huffington Foundation to H.J.B; NIH grant R01NS079618 to M. Sardiello and NIH grant R01NS069880 to S.Z. Publisher Copyright: {\textcopyright} 2019, {\textcopyright} 2019 Informa UK Limited, trading as Taylor & Francis Group.",
year = "2019",
month = jul,
day = "3",
doi = "10.1080/15548627.2019.1580103",
language = "English",
volume = "15",
pages = "1214--1233",
journal = "Autophagy",
issn = "1554-8627",
number = "7",
}