Tau interactome and RNA binding proteins in neurodegenerative diseases

Kavanagh, Tomas; Halder, Aditi; Drummond, Eleanor

doi:10.1186/s13024-022-00572-6

Cited by 39 publications

(55 citation statements)

References 126 publications

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“…However, despite the common Tau neuropathology, numerous studies have shown that Tau is processed distinctly in each of these conditions, which is reflected in differences in inclusion morphology, biochemical profile, and ultrastructure among the Tauopathies including PSP (Arakhamia et al, 2020;Falcon et al, 2019;Falcon, Zhang, Schweighauser, et al, 2018;Shi et al, 2021;Taniguchi-Watanabe et al, 2016). This is also supported by comparative interactome studies of human and rodent tau protein networks that show distinct differences in their aggresome profiles (Kavanagh et al, 2022), which potentially makes studying cellular mechanisms of the human condition difficult to recapitulate in rodent models.…”

Section: Introductionmentioning

confidence: 99%

Identification of phosphorylated tau protein interactors in progressive supranuclear palsy (PSP) reveals networks involved in protein degradation, stress response, cytoskeletal dynamics, metabolic processes, and neurotransmission

Radford

Rayner

Szwaja

et al. 2023

Journal of Neurochemistry

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Progressive supranuclear palsy (PSP) is a late‐onset neurodegenerative disease defined pathologically by the presence of insoluble phosphorylated‐Tau (p‐Tau) in neurons and glia. Identifying co‐aggregating proteins within p‐Tau inclusions may reveal important insights into processes affected by the aggregation of Tau. We used a proteomic approach, which combines antibody‐mediated biotinylation and mass spectrometry (MS) to identify proteins proximal to p‐Tau in PSP. Using this proof‐of‐concept workflow for identifying interacting proteins of interest, we characterized proteins proximal to p‐Tau in PSP cases, identifying >84% of previously identified interaction partners of Tau and known modifiers of Tau aggregation, while 19 novel proteins not previously found associated with Tau were identified. Furthermore, our data also identified confidently assigned phosphorylation sites that have been previously reported on p‐Tau. Additionally, using ingenuity pathway analysis (IPA) and human RNA‐seq datasets, we identified proteins previously associated with neurological disorders and pathways involved in protein degradation, stress responses, cytoskeletal dynamics, metabolism, and neurotransmission. Together, our study demonstrates the utility of biotinylation by antibody recognition (BAR) approach to answer a fundamental question to rapidly identify proteins in proximity to p‐Tau from post‐mortem tissue. The application of this workflow opens up the opportunity to identify novel protein targets to give us insight into the biological process at the onset and progression of tauopathies.

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Section: Introductionmentioning

confidence: 99%

Identification of phosphorylated tau protein interactors in progressive supranuclear palsy (PSP) reveals networks involved in protein degradation, stress response, cytoskeletal dynamics, metabolic processes, and neurotransmission

Radford

Rayner

Szwaja

et al. 2023

Journal of Neurochemistry

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“…Furthermore, an analysis to explore the differential proteome distributions across specific pathways/biofunctions revealed that most DEPs were related to changes in the adaptive immune system, the cellular response to chemical stress, programmed cell death or mitochondrial biogenesis. Our analysis also revealed that from the 484 dysregulated proteins, 8 proteins (including APOE 36 ) had been reported to functionally interact with tau and 27 proteins (including FUS 37 ) had also been found in the phosphorylated tau interactome of AD neurofibrillary tangles 27 . However, it is important to note that despite highlighting processes consistent with current concepts of neurodegenerative disease, a major limitation of the current approach is that we are unable to determine whether the observed changes in the proteome are related to the tau deposition.…”

Section: Discussionmentioning

confidence: 58%

Section: Discussionmentioning

confidence: 58%

4R-Tau seeding activity unravels molecular subtypes in patients with Progressive Supranuclear Palsy

Martinez-Valbuena,

Lee,

Santamaria

et al. 2023

Preprint

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Progressive Supranuclear palsy (PSP) is a 4-repeat (4-R) tauopathy. We hypothesized that the molecular diversity of tau could explain the heterogeneity seen in PSP disease progression. To test this hypothesis, we performed an extensive biochemical characterisation of the high molecular weight tau species (HMW-Tau) in 20 different brain regions of 25 PSP patients. We found a correlation between the HMW-Tau species and tau seeding capacity in the primary motor cortex, where we confirmed that an elevated 4R-Tau seeding activity correlates with a shorter disease duration. To identify factors that contribute to these differences, we performed proteomic and spatial transcriptomic analysis that revealed key mechanistic pathways, in particular those involving the immune system, that defined patients demonstrating high and low tau seeding capacity. These observations suggest that differences in the tau seeding activity may contribute to the considerable heterogeneity seen in disease progression of patients suffering from PSP.

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“…RPS27A has been linked to mild cognitive impairment (MCI) and AD [31, 32]. It has also been shown to interact with tau and lead to microglial activation that triggers subsequent widespread neurodegeneration [33, 34]. Both MRPL50 and NDUFB3 have been implicated in AD, glaucoma, and age-related neurodegeneration [35, 36].…”

Section: Discussionmentioning

confidence: 99%

Blood-based transcriptomic biomarkers are predictive of neurodegeneration rather than Alzheimer’s disease

Shvetcov,

Thomson,

Spathos

et al. 2023

Preprint

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Alzheimers disease (AD) is a growing global health crisis, affecting millions and incurring substantial economic costs. However, clinical diagnosis remains challenging, with misdiagnoses and underdiagnoses prevalent. There is an increased focus on putative, blood-based biomarkers that may be useful for the diagnosis, as well as early detection, of AD. In the present study, we used an unbiased combination of machine learning and functional network analyses to identify blood gene biomarker candidates in AD. Using supervised machine learning, we also determine whether these candidates were indeed unique to AD or whether they were indicative of other neurodegenerative diseases Parkinsons disease (PD) and amyotrophic lateral sclerosis (ALS). Our analyses showed that genes involved in spliceosome assembly, RNA binding, transcription, protein synthesis, mitoribosomes, and NADH dehydrogenase were the best performing genes for identifying AD patients relative to cognitively healthy controls. This transcriptomic signature, however, was not unique to AD and subsequent machine learning showed that this signature could also predict PD and ALS relative to controls without neurodegenerative disease. Combined, our results suggest that mRNA from whole blood can indeed be used to screen for patients with neurodegeneration but may be less effective at diagnosing the specific neurodegenerative disease.

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Tau interactome and RNA binding proteins in neurodegenerative diseases

Cited by 39 publications

References 126 publications

Identification of phosphorylated tau protein interactors in progressive supranuclear palsy (PSP) reveals networks involved in protein degradation, stress response, cytoskeletal dynamics, metabolic processes, and neurotransmission

Identification of phosphorylated tau protein interactors in progressive supranuclear palsy (PSP) reveals networks involved in protein degradation, stress response, cytoskeletal dynamics, metabolic processes, and neurotransmission

4R-Tau seeding activity unravels molecular subtypes in patients with Progressive Supranuclear Palsy

Blood-based transcriptomic biomarkers are predictive of neurodegeneration rather than Alzheimer’s disease

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