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Alpha-synuclein and tau: teammates in neurodegeneration?

ABSTRACT: The accumulation of ?-synuclein aggregates is the hallmark of Parkinson's disease, and more generally of synucleinopathies. The accumulation of tau aggregates however is classically found in the brains of patients with dementia, and this type of neuropathological feature specifically defines the tauopathies. Nevertheless, in numerous cases ?-synuclein positive inclusions are also described in tauopathies and vice versa, suggesting a co-existence or crosstalk of these proteinopathies. Interestingly, ?-synuclein and tau share striking common characteristics suggesting that they may work in concord. Tau and ?-synuclein are both partially unfolded proteins that can form toxic oligomers and abnormal intracellular aggregates under pathological conditions. Furthermore, mutations in either are responsible for severe dominant familial neurodegeneration. Moreover, tau and ?-synuclein appear to promote the fibrillization and solubility of each other in vitro and in vivo. This suggests that interactions between tau and ?-synuclein form a deleterious feed-forward loop essential for the development and spreading of neurodegeneration. Here, we review the recent literature with respect to elucidating the possible links between ?-synuclein and tau.

SUBMITTER: Moussaud S

PROVIDER: S-EPMC4230508 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature

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Alpha-synuclein and tau: teammates in neurodegeneration?

Moussaud Simon S Jones Daryl R DR Moussaud-Lamodière Elisabeth L EL Delenclos Marion M Ross Owen A OA McLean Pamela J PJ

Molecular neurodegeneration 20141029

The accumulation of α-synuclein aggregates is the hallmark of Parkinson's disease, and more generally of synucleinopathies. The accumulation of tau aggregates however is classically found in the brains of patients with dementia, and this type of neuropathological feature specifically defines the tauopathies. Nevertheless, in numerous cases α-synuclein positive inclusions are also described in tauopathies and vice versa, suggesting a co-existence or crosstalk of these proteinopathies. Interesting ...[more]

PMID: 25352339

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Project description:The abnormal accumulation of the tau protein into aggregates is a hallmark in neurodegenerative diseases collectively known as tauopathies. In normal conditions, tau binds off and on microtubules aiding in their assembly and stability dependent on the phosphorylation state of the protein. In disease-affected neurons, hyperphosphorylation leads to the accumulation of the tau protein into aggregates, mainly neurofibrillary tangles (NFT) which have been seen to colocalise with other protein aggregates in neurodegeneration. One such protein is α-synuclein, the main constituent of Lewy bodies (LB), a hallmark of Parkinson's disease (PD). In many neurodegenerative diseases, including PD, the colocalisation of tau and α-synuclein has been observed, suggesting possible interactions between the two proteins. To explore the cytotoxicity and interactions between these two proteins, we expressed full length human tau and α-synuclein in Dictyostelium discoideum alone, and in combination. We show that tau is phosphorylated in D. discoideum and colocalises closely (within 40 nm) with tubulin throughout the cytoplasm of the cell as well as with α-synuclein at the cortex. Expressing wild type α-synuclein alone caused inhibited growth on bacterial lawns, phagocytosis and intracellular Legionella proliferation rates, but activated mitochondrial respiration and non-mitochondrial oxygen consumption. The expression of tau alone impaired multicellular morphogenesis, axenic growth and phototaxis, while enhancing intracellular Legionella proliferation. Direct respirometric assays showed that tau impairs mitochondrial ATP synthesis and increased the "proton leak," while having no impact on respiratory complex I or II function. In most cases depending on the phenotype, the coexpression of tau and α-synuclein exacerbated (phototaxis, fruiting body morphology), or reversed (phagocytosis, growth on plates, mitochondrial respiratory function, Legionella proliferation) the defects caused by either tau or α-synuclein expressed individually. Proteomics data revealed distinct patterns of dysregulation in strains ectopically expressing tau or α-synuclein or both, but down regulation of expression of cytoskeletal proteins was apparent in all three groups and most evident in the strain expressing both proteins. These results indicate that tau and α-synuclein exhibit different but overlapping patterns of intracellular localisation, that they individually exert distinct but overlapping patterns of cytotoxic effects and that they interact, probably physically in the cell cortex as well as directly or indirectly in affecting some phenotypes. The results show the efficacy of using D. discoideum as a model to study the interaction of proteins involved in neurodegeneration.

Project description:BackgroundNeuronal dysfunction and degeneration linked to α-synuclein (αS) pathology is thought to be responsible for the progressive nature of Parkinson's disease and related dementia with Lewy bodies. Studies have indicated bidirectional pathological relationships between αS pathology and tau abnormalities. We recently showed that A53T mutant human αS (HuαS) can cause post-synaptic and cognitive deficits that require microtubule-associated protein tau expression. However, the role of tau in the development of αS pathology and subsequent neuronal dysfunction has been controversial. Herein, we set out to determine the role of tau in the onset and progression of αS pathology (α-synucleinopathy) using a transgenic mouse model of α-synucleinopathy lacking mouse tau expression.MethodsTransgenic mice expressing A53T mutant HuαS (TgA53T) were crossed with mTau-/- mice to generate TgA53T/mTau-/-. To achieve more uniform induction of α-synucleinopathy in mice, we used intramuscular injections of αS preformed fibrils (PFF) in non-transgenic (nTg), TgA53T, TgA53T/mTau-/-, and mTau-/- mice. Motor behavior was analyzed at 70 days post inoculation (dpi) of PFF and tissues for biochemical and neuropathological analysis were collected at 40 dpi, 70 dpi, and end stage.ResultsLoss of tau expression significantly delayed the onset of motor deficits in the TgA53T model and the progression of α-synucleinopathy disease, as evidenced by a significant reduction in histopathological and behavioral markers of neurodegeneration and disease, and a significant improvement in survival. In vitro application of PFF to primary mouse hippocampal neurons demonstrated no changes in PFF uptake and processing or pS129 αS aggregation as a function of tau expression. However, PFF-induced neurotoxicity, including morphological deficits in nTg neurons, was prevented with tau removal.ConclusionsCollectively, our data suggest that tau is likely acting downstream of αS pathology to affect neuronal homeostasis and survival. This work further supports the investigation of tau in α-synucleinopathies to identify novel disease-modifying therapeutic strategies.

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Alpha-synuclein and tau: teammates in neurodegeneration?

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Alpha-synuclein and tau: teammates in neurodegeneration?

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