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Autophagy. 2019 Jul;15(7):1214-1233. doi: 10.1080/15548627.2019.1580103. Epub 2019 Feb 20.

VAMP associated proteins are required for autophagic and lysosomal degradation by promoting a PtdIns4P-mediated endosomal pathway.

Author information

1
a Program in Developmental Biology , Baylor College of Medicine , Houston , TX , USA.
2
b Department of Molecular and Human Genetics , Baylor College of Medicine , Houston , TX , USA.
3
c The Brown Foundation Institute of Molecular Medicine , University of Texas McGovern Medical School at Houston , Houston , TX , USA.
4
d Department of Neurobiology and Anatomy , University of Texas McGovern Medical School at Houston , Houston , TX , USA.
5
e Programs in Genetics & Epigenetics and Neuroscience , University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences (MD Anderson UTHealth GSBS) , Houston , TX , USA.
6
f Texas Children's Hospital , Jan and Dan Duncan Neurological Research Institute , Houston , TX , USA.
7
g Department of Neuroscience , Baylor College of Medicine , Houston , TX , USA.
8
h Baylor College of Medicine , Howard Hughes Medical Institute , Houston , TX , USA.

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; autophagy

PMID:
30741620
PMCID:
PMC6613884
[Available on 2020-02-20]
DOI:
10.1080/15548627.2019.1580103

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