ArticleScience translational medicine2019
A farnesyltransferase inhibitor activates lysosomes and reduces tau pathology in mice with tauopathy.
Article in Science translational medicine, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 54 papers.
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Who cites it
54 citing papers in PubMed, 101 citations in OpenAlex.
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- Organotellurium Probes Enable One-step Single-cell Analysis of Post-translational Modification.Journal of the American Chemical Society · 2026Article
- Hippocampus-targeted BDNF gene therapy to rescue cognitive impairments of Alzheimer's disease in multiple mouse models.Genes & diseases · 2026Article
- Statins and genetic inhibition of the mevalonate pathway activate an ATF3-STMN2 regenerative program.bioRxiv : the preprint server for biology · 2026Article
- Discovery of TDP-43 aggregation inhibitorsbioRxiv : the preprint server for biology · 2026Article
- Enhanced lysosomal activity prevents infection with PrPThe Journal of biological chemistry · 2026Article
- Targeting protein aggregate co-pathologies in neurodegeneration: a viable therapeutic strategy?Molecular neurodegeneration advances · 2026Review
- LRRK2 kinase-mediated accumulation of lysosome-associated phospho-Rabs in tauopathies and synucleinopathies.Acta neuropathologica · 2025Article
- Rare biochemical & genetic conditions: clues for broader mechanistic insights.Cellular and molecular life sciences : CMLS · 2025Review
- Regulation of glial ApoE secretion by the mevalonate pathway is independent of ApoE isoform.Journal of Alzheimer's disease : JAD · 2025Article
- The role of small GTPases in Alzheimer's disease tau pathologies.Frontiers in cellular neuroscience · 2025Review
- Oligodendrocyte Dysfunction in Tauopathy: A Less Explored Area in Tau-Mediated Neurodegeneration.Cells · 2024Review
- Genetic and pharmacological modulation of lamin A farnesylation determines its function and turnover.Aging cell · 2024Article
- Rhes, a striatal enriched protein, regulates post-translational small-ubiquitin-like-modifier (SUMO) modification of nuclear proteins and alters gene expression.Cellular and molecular life sciences : CMLS · 2024Article
- Curbing Rhes Actions: Mechanism-based Molecular Target for Huntington's Disease and Tauopathies.CNS & neurological disorders drug targets · 2024Review
- Recent Advances in the Treatment and Management of Alzheimer's Disease: A Precision Medicine Perspective.Current topics in medicinal chemistry · 2024Review
- Impaired Autophagic-Lysosomal Fusion in Parkinson's Patient Midbrain Neurons Occurs through Loss of ykt6 and Is Rescued by Farnesyltransferase Inhibition.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2023Article
- Article
- Defective proteostasis in induced pluripotent stem cell models of frontotemporal lobar degeneration.Translational psychiatry · 2022Article
- Review
Corrections and comments
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Authors and funding
22 authors at 6 institutions in 2 countries.
Funding
Abstract
Tau inclusions are a shared feature of many neurodegenerative diseases, among them frontotemporal dementia caused by tau mutations. Treatment approaches for these conditions include targeting posttranslational modifications of tau proteins, maintaining a steady-state amount of tau, and preventing its tendency to aggregate. We discovered a new regulatory pathway for tau degradation that operates through the farnesylated protein, Rhes, a GTPase in the Ras family. Here, we show that treatment with the farnesyltransferase inhibitor lonafarnib reduced Rhes and decreased brain atrophy, tau inclusions, tau sumoylation, and tau ubiquitination in the rTg4510 mouse model of tauopathy. In addition, lonafarnib treatment attenuated behavioral abnormalities in rTg4510 mice and reduced microgliosis in mouse brain. Direct reduction of Rhes in the rTg4510 mouse by siRNA reproduced the results observed with lonafarnib treatment. The mechanism of lonafarnib action mediated by Rhes to reduce tau pathology was shown to operate through activation of lysosomes. We finally showed in mouse brain and in human induced pluripotent stem cell-derived neurons a normal developmental increase in Rhes that was initially suppressed by tau mutations. The known safety of lonafarnib revealed in human clinical trials for cancer suggests that this drug could be repurposed for treating tauopathies.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.