ArticleThe Journal of neuroscience : the official journal of the Society for Neuroscience2018
A53T Mutant Alpha-Synuclein Induces Tau-Dependent Postsynaptic Impairment Independently of Neurodegenerative Changes.
Article in The Journal of neuroscience : the official journal of the Society for Neuroscience, 2018. 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, 85 citations in OpenAlex.
- Genetics of α-Synuclein: The Prime Pathological Player of Parkinson's Disease.Neurotoxicity research · 2026Review
- When Pathologies Collide: The Intersection of Tau and Alpha-Synuclein in Neurodegenerative Diseases.Molecular neurobiology · 2026Review
- Review
- High-frequency oscillations arise through distinct mechanisms in models of α- synucleinopathy and channelopathy-induced epilepsy.Research square · 2026Article
- Amyloid and Tau Co-pathology in Parkinson Disease and Atypical Parkinsonism.Current neurology and neuroscience reports · 2026Review
- Deciphering the Neuroautophagic Interactome: Molecular Circuits Linking Selective Autophagy to Neuropathological Cascades in Neurological Disorders.International journal of biological sciences · 2026Review
- Epilepsy and EEG abnormalities in neurodegenerative dementias: toward a system epilepsy framework.Frontiers in aging neuroscience · 2026Review
- Disrupting α-Synuclein-ClpP interaction restores mitochondrial function and attenuates neuropathology in Parkinson's disease models.Molecular neurodegeneration · 2025Article
- Tau protein: Physiological functions and multifaceted roles in neurodegenerative and psychiatric disorders.Genomic psychiatry : advancing science from genes to society · 2025Article
- Human Wild-Type α-Synuclein Drives Progressive Tau Pathology in a Disease-Relevant Mouse Model of Synucleinopathy.Research square · 2025Article
- Article
- Soluble and Insoluble Lysates from the Human A53T Mutant α-Synuclein Transgenic Mouse Model Induces α-Synucleinopathy Independent of Injection Site.International journal of molecular sciences · 2025Article
- α-synuclein and tau: interactions, cross-seeding, and the redefinition of synucleinopathies as complex proteinopathies.Frontiers in neuroscience · 2025Review
- Novel Therapeutic Horizons:Biomolecules · 2024Review
- G272V and P301L Mutations Induce Isoform Specific Tau Mislocalization to Dendritic Spines and Synaptic Dysfunctions in Cellular Models of 3R and 4R Tau Frontotemporal Dementia.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2024Article
- A stem cell-based assay platform demonstrates alpha-synuclein dependent synaptic dysfunction in patient-derived cortical neurons.NPJ Parkinson's disease · 2024Article
- Disruption of Dopamine Homeostasis Associated with Alteration of Proteins in Synaptic Vesicles: A Putative Central Mechanism of Parkinson's Disease Pathogenesis.Aging and disease · 2024Review
- Pathological and physiological functional cross-talks of α-synuclein and tau in the central nervous system.Neural regeneration research · 2024Review
- In vitro modulation of mTOR and mGlur5 influence α-synuclein accumulation.Molecular brain · 2024Article
- Latest advances in mechanisms of epileptic activity in Alzheimer's disease and dementia with Lewy Bodies.Frontiers in neurology · 2024Review
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Authors and funding
11 authors at 3 institutions in 2 countries.
Funding
Abstract
Abnormalities in α-synuclein are implicated in the pathogenesis of Parkinson's disease (PD). Because α-synuclein is highly concentrated within presynaptic terminals, presynaptic dysfunction has been proposed as a potential pathogenic mechanism. Here, we report novel, tau-dependent, postsynaptic deficits caused by A53T mutant α-synuclein, which is linked to familial PD. We analyzed synaptic activity in hippocampal slices and cultured hippocampal neurons from transgenic mice of either sex expressing human WT, A53T, and A30P α-synuclein. Increased α-synuclein expression leads to decreased spontaneous synaptic vesicle release regardless of genotype. However, only those neurons expressing A53T α-synuclein exhibit postsynaptic dysfunction, including decreased miniature postsynaptic current amplitude and decreased AMPA to NMDA receptor current ratio. We also found that long-term potentiation and spatial learning were impaired by A53T α-synuclein expression. Mechanistically, postsynaptic dysfunction requires glycogen synthase kinase 3β-mediated tau phosphorylation, tau mislocalization to dendritic spines, and calcineurin-dependent AMPA receptor internalization. Previous studies reveal that human A53T α-synuclein has a high aggregation potential, which may explain the mutation's unique capacity to induce postsynaptic deficits. However, patients with sporadic PD with severe tau pathology are also more likely to have early onset cognitive decline. Our results here show a novel, functional role for tau: mediating the effects of α-synuclein on postsynaptic signaling. Therefore, the unraveled tau-mediated signaling cascade may contribute to the pathogenesis of dementia in A53T α-synuclein-linked familial PD cases, as well as some subgroups of PD cases with extensive tau pathology.
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