期刊
JOURNAL OF CELL SCIENCE
卷 132, 期 7, 页码 -出版社
COMPANY BIOLOGISTS LTD
DOI: 10.1242/jcs.220061
关键词
Endolysosomes; Neuritogenesis; NSC34 cells; Neurodegenerative diseases; Phosphatidylinositol-4-phosphate
类别
资金
- PNR-Consiglio Nazionale delle Ricerche [Ageing Program 2012-2014]
- Fondazione Regionale per la Ricerca Biomedica [TRANS-ALS grant] [2015-0023]
- Fondazione Telethon
- European Research Council [670881]
- Associazione Italiana per la Ricerca sul Cancro
- Universita degli Studi di Milano
- Associazione Italiana per la Miastenia
- Regione Lombardia [Amanda Project] [CUP_B42F16000440005]
- Fondazione Antonio Carlo Monzino
- European Research Council (ERC) [670881] Funding Source: European Research Council (ERC)
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.
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