Role of the Lipid Membrane and Membrane Proteins in Tau Pathology

Bok, Eugene; Leem, Eunju; Lee, Boram; Lee, Ji Min; Yoo, Chang Jae; Lee, Eun Mi; Kim, Jae Kwang

doi:10.3389/fcell.2021.653815

Cited by 33 publications

(35 citation statements)

References 147 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Although there are conflicting reports on the role of cholesterol in AD, it is not difficult to envision how reduced neuronal cholesterol levels can lead to the neuropathological impairments which are associated with AD, resulting in the brain dysfunction [ 16 , 27 , 33 , 40 , 49 , 53 ]. Very importantly, increasing evidences reveal that the neuronal cholesterol deficit/loss could induce the disruption of membrane lipid rafts and/or intracellular organelles, and eventually leads to the formation of pathological impairments, which are obviously linked to the pathological changes which are associated with the pathogenesis of AD and other neurodegenerative diseases [ 1 , 5 , 9 , 16 , 21 , 24 , 27 , 33 , 36 , 40 , 44 , 74 , 75 , 91 , 93 , 99 , 115 , 119 ]. Taking together, compelling evidences suggest that the brain cholesterol deficiency could contribute to AD pathogenesis.…”

Section: Widen the View On Ad: Brain Cholesterol Level And Admentioning

confidence: 99%

The role of DHCR24 in the pathogenesis of AD: re-cognition of the relationship between cholesterol and AD pathogenesis

Bai

Mai

Yao

et al. 2022

acta neuropathol commun

View full text Add to dashboard Cite

Previous studies show that 3β-hydroxysterol-Δ24 reductase (DHCR24) has a remarked decline in the brain of AD patients. In brain cholesterol synthetic metabolism, DHCR24 is known as the heavily key synthetase in cholesterol synthesis. Moreover, mutations of DHCR24 gene result in inhibition of the enzymatic activity of DHCR24, causing brain cholesterol deficiency and desmosterol accumulation. Furthermore, in vitro studies also demonstrated that DHCR24 knockdown lead to the inhibition of cholesterol synthesis, and the decrease of plasma membrane cholesterol and intracellular cholesterol level. Obviously, DHCR24 could play a crucial role in maintaining cholesterol homeostasis via the control of cholesterol synthesis. Over the past two decades, accumulating data suggests that DHCR24 activity is downregulated by major risk factors for AD, suggesting a potential link between DHCR24 downregulation and AD pathogenesis. Thus, the brain cholesterol loss seems to be induced by the major risk factors for AD, suggesting a possible causative link between brain cholesterol loss and AD. According to previous data and our study, we further found that the reduced cholesterol level in plasma membrane and intracellular compartments by the deficiency of DHCR24 activity obviously was involved in β-amyloid generation, tau hyperphosphorylation, apoptosis. Importantly, increasing evidences reveal that the brain cholesterol loss and lipid raft disorganization are obviously linked to neuropathological impairments which are associated with AD pathogenesis. Therefore, based on previous data and research on DHCR24, we suppose that the brain cholesterol deficiency/loss might be involved in the pathogenesis of AD.

show abstract

Section: Widen the View On Ad: Brain Cholesterol Level And Admentioning

confidence: 99%

The role of DHCR24 in the pathogenesis of AD: re-cognition of the relationship between cholesterol and AD pathogenesis

Bai

Mai

Yao

et al. 2022

acta neuropathol commun

View full text Add to dashboard Cite

show abstract

“…Lipid metabolism has been found to be dysregulated in association with tau pathology in AD and α-synuclein in PD and synucleinopathies. For reviews see ( Bok et al, 2021 ) and ( Alecu and Bennett, 2019 ). Lewy bodies, the α-synuclein-containing aggregates that are the pathological hallmark of PD, contain high lipid content and lipid membranes ( Shahmoradian et al, 2019 ), while membrane lipids such as those associated with cholesterol have been associated with PHF in AD brains ( Gellermann et al, 2006 ).…”

Section: Resultsmentioning

confidence: 99%

Interactions and Cytotoxicity of Human Neurodegeneration- Associated Proteins Tau and α-Synuclein in the Simple Model Dictyostelium discoideum

Mroczek

Fernando

Fisher

et al. 2021

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

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.

show abstract

“…Pathogenic tau, Aβ, and other proteins can be spread by transmitting from one neuron to another by exocytosis or via synapses or extracellular vesicles (EV) in the central nervous system (CNS), or transferring to the CNS from the peripheral nervous system [ 8 , 9 , 10 , 11 , 12 , 13 ]. The transmission results in amplification of the pathogenic proteins.…”

Section: Spread Of Pathogenic Tau and Aβ In The Brainmentioning

confidence: 99%

“…Tau is found in the body fluids such as cerebrospinal fluid and blood. Spatiotemporal spreading and distribution of pathogenic tau correlates with cognitive decline in AD patients [ 8 , 9 , 10 , 11 ]. It is postulated that when tau is misfolded in the neurons, it can be released from one neuron and transmitted to another.…”

Section: Spread Of Pathogenic Tau and Aβ In The Brainmentioning

confidence: 99%

WWOX and Its Binding Proteins in Neurodegeneration

Hsu

Lee

Sun

et al. 2021

Cells

View full text Add to dashboard Cite

WW domain-containing oxidoreductase (WWOX) is known as one of the risk factors for Alzheimer’s disease (AD), a neurodegenerative disease. WWOX binds Tau via its C-terminal SDR domain and interacts with Tau phosphorylating enzymes ERK, JNK, and GSK-3β, and thereby limits AD progression. Loss of WWOX in newborns leads to severe neural diseases and early death. Gradual loss of WWOX protein in the hippocampus and cortex starting from middle age may slowly induce aggregation of a protein cascade that ultimately causes accumulation of extracellular amyloid beta plaques and intracellular tau tangles, along with reduction in inhibitory GABAergic interneurons, in AD patients over 70 years old. Age-related increases in pS14-WWOX accumulation in the brain promotes neuronal degeneration. Suppression of Ser14 phosphorylation by a small peptide Zfra leads to enhanced protein degradation, reduction in NF-κB-mediated inflammation, and restoration of memory loss in triple transgenic mice for AD. Intriguingly, tumor suppressors p53 and WWOX may counteract each other in vivo, which leads to upregulation of AD-related protein aggregation in the brain and lung. WWOX has numerous binding proteins. We reported that the stronger the binding between WWOX and its partners, the better the suppression of cancer growth and reduction in inflammation. In this regard, the stronger complex formation between WWOX and partners may provide a better blockade of AD progression. In this review, we describe whether and how WWOX and partner proteins control inflammatory response and protein aggregation and thereby limit AD progression.

show abstract

Role of the Lipid Membrane and Membrane Proteins in Tau Pathology

Cited by 33 publications

References 147 publications

The role of DHCR24 in the pathogenesis of AD: re-cognition of the relationship between cholesterol and AD pathogenesis

The role of DHCR24 in the pathogenesis of AD: re-cognition of the relationship between cholesterol and AD pathogenesis

Interactions and Cytotoxicity of Human Neurodegeneration- Associated Proteins Tau and α-Synuclein in the Simple Model Dictyostelium discoideum

WWOX and Its Binding Proteins in Neurodegeneration

Contact Info

Product

Resources

About