ArticleHuman molecular genetics2012
Neuronal expression of Fig4 is both necessary and sufficient to prevent spongiform neurodegeneration.
Article in Human molecular genetics, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 39 papers.
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Who cites it
39 citing papers in PubMed, 61 citations in OpenAlex.
- Beyond Neurodegeneration: White Matter Vacuolation as a Primary Myelin Defect.International journal of molecular sciences · 2026Review
- Transient receptor potential vanilloid channel 2 contributes to multi-modal endoplasmic reticulum and perinuclear space dilations that can also be observed in prion-infected mice.Acta neuropathologica · 2025Article
- Identification and splicing analysis of the first deep intronicFrontiers in genetics · 2025Article
- The role of autophagy in the pathogenesis and treatment of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).Autophagy reports · 2025Review
- Altered phenotypes due to genetic interaction between the mouse phosphoinositide biosynthesis genes Fig4 and Pip4k2c.G3 (Bethesda, Md.) · 2023Article
- Chloroquine corrects enlarged lysosomes in FIG4 null cells and reduces neurodegeneration in Fig4 null mice.Molecular genetics and metabolism · 2022Article
- Autophagy Dysfunction in ALS: from Transport to Protein Degradation.Journal of molecular neuroscience : MN · 2022Review
- Modelling amyotrophic lateral sclerosis in rodents.Nature reviews. Neuroscience · 2022Review
- Mechanisms and Treatments in Demyelinating CMT.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2021Review
- Animal Models as a Tool to Design Therapeutical Strategies for CMT-like Hereditary Neuropathies.Brain sciences · 2021Review
- AAV9-mediated FIG4 delivery prolongs life span in Charcot-Marie-Tooth disease type 4J mouse model.The Journal of clinical investigation · 2021Article
- Adeno-associated virus gene therapy to the rescue for Charcot-Marie-Tooth disease type 4J.The Journal of clinical investigation · 2021Article
- Neuron-specific Kv1.1 deficiency is sufficient to cause epilepsy, premature death, and cardiorespiratory dysregulation.Neurobiology of disease · 2020Article
- Lysosomal size matters.Traffic (Copenhagen, Denmark) · 2020Review
- Severe Consequences of SAC3/FIG4 Phosphatase Deficiency to Phosphoinositides in Patients with Charcot-Marie-Tooth Disease Type-4J.Molecular neurobiology · 2019Article
- CRISPR knockout screen implicates three genes in lysosome function.Scientific reports · 2019Article
- 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
- Neuropathology of childhood-onset basal ganglia degeneration caused by mutation ofAnnals of clinical and translational neurology · 2017Article
- Biallelic Mutations of VAC14 in Pediatric-Onset Neurological Disease.American journal of human genetics · 2016Article
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Authors and funding
8 authors at 1 institution in 1 country.
Funding
Abstract
FIG4 is a ubiquitously expressed phosphatase that, in complex with FAB1/PIKFYVE and VAC14, regulates the biosynthesis of the signaling lipid PI(3,5)P(2). Null mutation of Fig4 in the mouse results in spongiform degeneration of brain and peripheral ganglia, defective myelination and juvenile lethality. Partial loss-of-function of human FIG4 results in a severe form of Charcot-Marie-Tooth neuropathy. Neurons from null mice contain enlarged vacuoles derived from the endosome/lysosome pathway, and astrocytes accumulate proteins involved in autophagy. Other cellular defects include astrogliosis and microgliosis. To distinguish the contributions of neurons and glia to spongiform degeneration in the Fig4 null mouse, we expressed Fig4 under the control of the neuron-specific enolase promoter and the astrocyte-specific glial fibrillary acidic protein promoter in transgenic mice. Neuronal expression of Fig4 was sufficient to rescue cellular and neurological phenotypes including spongiform degeneration, gliosis and juvenile lethality. In contrast, expression of Fig4 in astrocytes prevented accumulation of autophagy markers and microgliosis but did not prevent spongiform degeneration or lethality. To confirm the neuronal origin of spongiform degeneration, we generated a floxed allele of Fig4 and crossed it with mice expressing the Cre recombinase from the neuron-specific synapsin promoter. Mice with conditional inactivation of Fig4 in neurons developed spongiform degeneration and the full spectrum of neurological abnormalities. The data demonstrate that expression of Fig4 in neurons is necessary and sufficient to prevent spongiform degeneration. Therapy for patients with FIG4 deficiency will therefore require correction of the deficiency in neurons.
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