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VAPB depletion alters neuritogenesis and phosphoinositide balance in motoneuron-like cells: relevance to VAPB-linked amyotrophic lateral sclerosis.
- Source :
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Journal of cell science [J Cell Sci] 2019 Apr 03; Vol. 132 (7). Date of Electronic Publication: 2019 Apr 03. - Publication Year :
- 2019
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Abstract
- VAPB and VAPA are ubiquitously expressed endoplasmic reticulum membrane proteins that play key roles in lipid exchange at membrane contact sites. A mutant, aggregation-prone, form of VAPB (P56S) is linked to a dominantly inherited form of amyotrophic lateral sclerosis; however, it has been unclear whether its pathogenicity is due to toxic gain of function, to negative dominance, or simply to insufficient levels of the wild-type protein produced from a single allele (haploinsufficiency). To investigate whether reduced levels of functional VAPB, independently from the presence of the mutant form, affect the physiology of mammalian motoneuron-like cells, we generated NSC34 clones, from which VAPB was partially or nearly completely depleted. VAPA levels, determined to be over fourfold higher than those of VAPB in untransfected cells, were unaffected. Nonetheless, cells with even partially depleted VAPB showed an increase in Golgi- and acidic vesicle-localized phosphatidylinositol-4-phosphate (PI4P) and reduced neurite extension when induced to differentiate. Conversely, the PI4 kinase inhibitors PIK93 and IN-10 increased neurite elongation. Thus, for long-term survival, motoneurons might require the full dose of functional VAPB, which may have unique function(s) that VAPA cannot perform.<br />Competing Interests: Competing interestsThe authors declare no competing or financial interests.<br /> (© 2019. Published by The Company of Biologists Ltd.)
- Subjects :
- Amyotrophic Lateral Sclerosis genetics
Amyotrophic Lateral Sclerosis pathology
Animals
Golgi Apparatus metabolism
HeLa Cells
Humans
Motor Neurons pathology
Mutation
Neurites pathology
Rats
Vesicular Transport Proteins genetics
Amyotrophic Lateral Sclerosis metabolism
Endoplasmic Reticulum metabolism
Motor Neurons metabolism
Neurites metabolism
Phosphatidylinositols metabolism
Vesicular Transport Proteins metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1477-9137
- Volume :
- 132
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- Journal of cell science
- Publication Type :
- Academic Journal
- Accession number :
- 30745341
- Full Text :
- https://doi.org/10.1242/jcs.220061