ArticleHuman molecular genetics2016
Rescue of neurodegeneration in the Fig4 null mouse by a catalytically inactive FIG4 transgene.
Article in Human molecular genetics, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 21 citations in OpenAlex.
- Homeostatic Influence of Fig4 Outside of the Fab1-Vac14-Fig4 Complex in Saccharomyces cerevisiae.Molecular microbiology · 2025Article
- The role of autophagy in the pathogenesis and treatment of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).Autophagy reports · 2025Review
- Exploring the phenotypic spectrum and osteopenia mechanisms in Yunis-Varón syndrome.Genetics in medicine open · 2024Article
- The endolysosomal pathway and ALS/FTD.Trends in neurosciences · 2023Review
- Chloroquine corrects enlarged lysosomes in FIG4 null cells and reduces neurodegeneration in Fig4 null mice.Molecular genetics and metabolism · 2022Article
- Adeno-associated virus gene therapy to the rescue for Charcot-Marie-Tooth disease type 4J.The Journal of clinical investigation · 2021Article
- A dysfunctional endolysosomal pathway common to two sub-types of demyelinating Charcot-Marie-Tooth disease.Acta neuropathologica communications · 2020Article
- Roles for a lipid phosphatase in the activation of its opposing lipid kinase.Molecular biology of the cell · 2020Article
- Cerebral hypomyelination associated with biallelic variants of FIG4.Human mutation · 2019Article
- Protective role of the lipid phosphatase Fig4 in the adult nervous system.Human molecular genetics · 2018Article
- Lysosome enlargement during inhibition of the lipid kinase PIKfyve proceeds through lysosome coalescence.Journal of cell science · 2018Article
- A New Mutation in FIG4 Causes a Severe Form of CMT4J Involving TRPV4 in the Pathogenic Cascade.Journal of neuropathology and experimental neurology · 2017Article
- The role of the PI(3,5)PMolecular and biochemical parasitology · 2017Article
- Biallelic Mutations of VAC14 in Pediatric-Onset Neurological Disease.American journal of human genetics · 2016Article
- FIG4 regulates lysosome membrane homeostasis independent of phosphatase function.Human molecular genetics · 2016Article
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Authors and funding
7 authors at 1 institution in 1 country.
Funding
Abstract
The lipid phosphatase FIG4 is a subunit of the protein complex that regulates biosynthesis of the signaling lipid PI(3,5)P2. Mutations of FIG4 result in juvenile lethality and spongiform neurodegeneration in the mouse, and are responsible for the human disorders Charcot-Marie-Tooth disease, Yunis-Varon syndrome and polymicrogyria with seizures. We previously demonstrated that conditional expression of a wild-type FIG4 transgene in neurons is sufficient to rescue most of the abnormalities of Fig4 null mice, including juvenile lethality and extensive neurodegeneration. To evaluate the contribution of the phosphatase activity to the in vivo function of Fig4, we introduced the mutation p.Cys486Ser into the Sac phosphatase active-site motif CX5RT. Transfection of the Fig4(Cys486Ser) cDNA into cultured Fig4(-/-) fibroblasts was effective in preventing vacuolization. The neuronal expression of an NSE-Fig4(Cys486Ser) transgene in vivo prevented the neonatal neurodegeneration and juvenile lethality seen in Fig4 null mice. These observations demonstrate that the catalytically inactive FIG4 protein provides significant function, possibly by stabilization of the PI(3,5)P2 biosynthetic complex and/or localization of the complex to endolysosomal vesicles. Despite this partial rescue, later in life the NSE-Fig4(Cys486Ser) transgenic mice display significant abnormalities that include hydrocephalus, defective myelination and reduced lifespan. The late onset phenotype of the NSE-Fig4(Cys486Ser) transgenic mice demonstrates that the phosphatase activity of FIG4 has an essential role in vivo.
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