ArticleMolecular neurodegeneration2015
Frontotemporal dementia-associated N279K tau mutant disrupts subcellular vesicle trafficking and induces cellular stress in iPSC-derived neural stem cells.
Article in Molecular neurodegeneration, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 51 papers.
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51 citing papers in PubMed, 101 citations in OpenAlex.
- Review
- Tauopathy strains differentially replicate in vitro in the presence of mutant tau monomer.Neurobiology of disease · 2025Article
- Lysosomes as Dynamic Regulators of Metabolic Signaling and Organ Physiology in Aging: From Mechanism to Therapy.Aging and disease · 2025Review
- Hippocampal mitophagy alterations in MAPT-associated frontotemporal dementia with parkinsonism.Acta neuropathologica communications · 2025Article
- Transgenic iPSC Lines with Genetically Encoded MitoTimer to Study Mitochondrial Biogenesis in Dopaminergic Neurons with Tauopathy.Biomedicines · 2025Article
- Dysregulation of REST and its target genes impacts the fate of neural progenitor cells in down syndrome.Scientific reports · 2025Article
- The restoration of REST inhibits reactivity of Down syndrome iPSC-derived astrocytes.Frontiers in molecular neuroscience · 2025Article
- Modeling Lewy body disease withScience advances · 2024Article
- Human Brain In Vitro Model for Pathogen Infection-Related Neurodegeneration Study.International journal of molecular sciences · 2024Review
- Endo-lysosomal dysfunction in neurodegenerative diseases: opinion on current progress and future direction in the use of exosomes as biomarkers.Philosophical transactions of the Royal Society of London. Series B, Biological sciences · 2024Review
- MAPT Mutations V337M and N297K Alter Organelle Trafficking in Frontotemporal Dementia Patient-Specific Motor Neurons.Biomedicines · 2024Article
- A Mutant Methionyl-tRNA Synthetase-Based toolkit to assess induced-Mesenchymal Stromal Cell secretome in mixed-culture disease models.Research square · 2023Article
- Clusters of co-abundant proteins in the brain cortex associated with fronto-temporal lobar degeneration.Alzheimer's research & therapy · 2023Article
- Single-cell transcriptomics reveal extracellular vesicles secretion with a cardiomyocyte proteostasis signature during pathological remodeling.Communications biology · 2023Article
- Defective proteostasis in induced pluripotent stem cell models of frontotemporal lobar degeneration.Translational psychiatry · 2022Article
- Genetic and Epigenetic Constructs of Progressive Supranuclear Palsy.Annals of neurosciences · 2022Review
- Exploring Neurofilament Light Chain and Exosomes in the Genetic Forms of Frontotemporal Dementia.Frontiers in neuroscience · 2022Review
- Apolipoprotein E regulates lipid metabolism and α-synuclein pathology in human iPSC-derived cerebral organoids.Acta neuropathologica · 2021Article
- Extracellular Vesicles-The Next Frontier in Endocrinology.Endocrinology · 2021Review
- Article
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17 authors at 3 institutions in 2 countries.
Funding
Abstract
backgroundPallido-ponto-nigral degeneration (PPND), a major subtype of frontotemporal dementia with parkinsonism related to chromosome 17 (FTDP-17), is a progressive and terminal neurodegenerative disease caused by c.837 T > G mutation in the MAPT gene encoding microtubule-associated protein tau (rs63750756; N279K). This MAPT mutation induces alternative splicing of exon 10, resulting in a modification of microtubule-binding region of tau. Although mutations in the MAPT gene have been linked to multiple tauopathies including Alzheimer's disease, frontotemporal dementia and progressive supranuclear palsy, knowledge regarding how tau N279K mutation causes PPND/FTDP-17 is limited.
resultsWe investigated the underlying disease mechanism associated with the N279K tau mutation using PPND/FTDP-17 patient-derived induced pluripotent stem cells (iPSCs) and autopsy brains. In iPSC-derived neural stem cells (NSCs), the N279K tau mutation induced an increased ratio of 4-repeat to 3-repeat tau and accumulation of stress granules indicating elevated cellular stress. More significant, NSCs derived from patients with the N279K tau mutation displayed impaired endocytic trafficking as evidenced by accumulation of endosomes and exosomes, and a reduction of lysosomes. Since there were no significant differences in cellular stress and distribution of subcellular organelles between control and N279K skin fibroblasts, N279K-related vesicle trafficking defects are likely specific to the neuronal lineage. Consistently, the levels of intracellular/luminal vesicle and exosome marker flotillin-1 were significantly increased in frontal and temporal cortices of PPND/FTDP-17 patients with the N279K tau mutation, events that were not seen in the occipital cortex which is the most spared cortical region in the patients.
conclusionTogether, our results demonstrate that alterations of intracellular vesicle trafficking in NSCs/neurons likely contribute to neurodegeneration as an important disease mechanism underlying the N279K tau mutation in PPND/FTDP-17.
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