ArticleThe Journal of neuroscience : the official journal of the Society for Neuroscience2021
Frontotemporal Lobar Dementia Mutant Tau Impairs Axonal Transport through a Protein Phosphatase 1γ-Dependent Mechanism.
Article in The Journal of neuroscience : the official journal of the Society for Neuroscience, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 26 citations in OpenAlex.
- Aberrant tau accumulation caused by MAPT mutations induces early pathological changes in axonal transport that are rescued by p38α inhibition.Nature neuroscience · 2026Article
- Sex-specific effects of acetylation on tauopathy in aging htau mice.Scientific reports · 2026Article
- Potential common pathogenesis of several neurodegenerative diseases.Neural regeneration research · 2026Article
- Inhibition of pathogenic tau signaling via blocking of the phosphatase-activating domain by novel small molecules.Frontiers in pharmacology · 2026Article
- Mutant Tau (P301L) Enhances Global Protein Translation in Differentiated SH-SY5Y Cells by Upregulating mTOR Signalling.International journal of molecular sciences · 2026Article
- Seeding Alzheimer's disease-associated tau pathology in MAPT knock-in primary neurons causes early axonopathy and synaptic dysfunction.Scientific reports · 2025Article
- BioID2-Based Tau Interactome Reveals Novel and Known Protein Interactions Associated with Multiple Cellular Pathways.Journal of proteome research · 2025Article
- Protein aggregation and neurodegenerative disease: Structural outlook for the novel therapeutics.Proteins · 2025Review
- Polyamination with spermidine enhances pathogenic tau conformations while reducing filamentous aggregate formation in vitro.The Biochemical journal · 2025Article
- Yi-Nao-Jie-Yu Prescription Relieves Post-Stroke Depression by Mitigating Ferroptosis in Hippocampal Neurons Via Activating the Nrf2/GPX4/SLC7A11 Pathway.Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology · 2025Article
- Distinct subcellular localization of tau and alpha-synuclein in lewy body disease.Acta neuropathologica communications · 2025Article
- Cellular and pathological functions of tau.Nature reviews. Molecular cell biology · 2024Review
- FTLD-MAPT mutations and short 5'UTR Tau mRNAs increase Tau translation.NAR molecular medicine · 2024Article
- Toxic effects of mutant huntingtin in axons are mediated by its proline-rich domain.Brain : a journal of neurology · 2024Article
- Biochemical approaches to assess the impact of post-translational modifications on pathogenic tau conformations using recombinant protein.Biochemical Society transactions · 2024Review
- Using Live-Cell Imaging to Measure the Effects of Pathological Proteins on Axonal Transport in Primary Hippocampal Neurons.Journal of visualized experiments : JoVE · 2023Article
- Disease-Associated Mutations in Tau Encode for Changes in Aggregate Structure Conformation.ACS chemical neuroscience · 2023Article
- Phosphomimetics at Ser199/Ser202/Thr205 in Tau Impairs Axonal Transport in Rat Hippocampal Neurons.Molecular neurobiology · 2023Article
- PP1γ regulates neuronal insulin signaling and aggravates insulin resistance leading to AD-like phenotypes.Cell communication and signaling : CCS · 2023Article
- Modulations of the neuronal trafficking of tissue-type plasminogen activator (tPA) influences glutamate release.Cell death & disease · 2023Article
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Authors and funding
9 authors at 4 institutions in 1 country.
Funding
Abstract
Pathologic tau modifications are characteristic of Alzheimer's disease and related dementias, but mechanisms of tau toxicity continue to be debated. Inherited mutations in tau cause early onset frontotemporal lobar dementias (FTLD-tau) and are commonly used to model mechanisms of tau toxicity in tauopathies. Previous work in the isolated squid axoplasm model demonstrated that several pathogenic forms of tau inhibit axonal transport through a mechanism involving activation of protein phosphatase 1 (PP1). Here, we determined that P301L and R5L FTLD mutant tau proteins elicit a toxic effect on axonal transport as monomeric proteins. We evaluated interactions of wild-type or mutant tau with specific PP1 isoforms (α, β, and γ) to examine how the interaction contributes to this toxic effect using primary rat hippocampal neurons from both sexes. Pull-down and bioluminescence resonance energy transfer experiments revealed selective interactions of wild-type tau with PP1α and PP1γ isoforms, but not PP1β, which were significantly increased by the P301L tau mutation. The results from proximity ligation assays confirmed the interaction in primary hippocampal neurons. Moreover, expression of FTLD-linked mutant tau in these neurons enhanced levels of active PP1, also increasing the pausing frequency of fluorescently labeled vesicles in both anterograde and retrograde directions. Knockdown of PP1γ, but not PP1α, rescued the cargo-pausing effects of P301L and R5L tau, a result replicated by deleting a phosphatase-activating domain in the amino terminus of P301L tau. These findings support a model of tau toxicity involving aberrant activation of a specific PP1γ-dependent pathway that disrupts axonal transport in neurons.
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