Tau Trimers Are the Minimal Propagation Unit Spontaneously Internalized to Seed Intracellular Aggregation

Mirbaha, Hilda; Holmes, Brandon B.; Sanders, David W.; Bieschke, Jan; Diamond, Marc I.

doi:10.1074/jbc.m115.652693

Cited by 190 publications

(197 citation statements)

References 40 publications

(49 reference statements)

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“…4B), suggesting that although extracellular tau species bind to the cell surface, the tau uptake process in HEK293T cells is not very rapid or efficient. Heparan sulfate proteoglycans (HSPGs), which are ubiquitously expressed on cell surfaces, mediate uptake of tau assemblies from monomers to oligomers and fibrils (Holmes et al, 2013;Mirbaha et al, 2015). An additional washing step with 20 µg/ml heparin further reduced the signal.…”

Section: A Sensitive Live-cell Assay For Monitoring Secretion Of Tau mentioning

confidence: 99%

FRMD4A-cytohesin signaling modulates cellular release of Tau

Nykänen

Brunello

et al. 2016

Journal of Cell Science

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One of the defining pathological features of Alzheimer's disease is the intraneuronal accumulation of tau (also known as MAPT) protein.Tau is also secreted from neurons in response to various stimuli and accumulates in the cerebrospinal fluid of Alzheimer's disease patients. Tau pathology might spread from cell to cell through a mechanism involving secretion and uptake. Here, we developed an assay to follow cellular release and uptake of tau dimers. Individual silencing of ten common late-onset Alzheimer's disease risk genes in HEK293T cells expressing the tau reporters suggested that FRMD4A is functionally linked to tau secretion. FRMD4A depletion by using RNA interference (RNAi) reduced and overexpression increased tau secretion. The activity of cytohesins, interactors of FRMD4A and guanine-nucleotide-exchange factors of Arf6, was necessary for FRMD4A-induced tau secretion. Increased Arf6 and cell polarity signaling through Par6 and atypical protein kinase Cζ (aPKCζ) stimulated tau secretion. In mature cortical neurons, FRMD4A RNAi or inhibition of cytohesins strongly upregulated secretion of endogenous tau. These results suggest that FRMD4A, a genetic risk factor for late-onset Alzheimer's disease, regulates tau secretion by activating cytohesin-Arf6 signaling. We conclude that genetic risk factors of Alzheimer's disease might modulate disease progression by altering tau secretion.

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Section: A Sensitive Live-cell Assay For Monitoring Secretion Of Tau mentioning

confidence: 99%

FRMD4A-cytohesin signaling modulates cellular release of Tau

Nykänen

Brunello

et al. 2016

Journal of Cell Science

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“…HEK293 cells and their derivatives, such as 293T and 293FT cells, have been extensively used as model cells for the expression of mutant proteins implicated in neurodegenerative disease, including expression of mutant Htt (Bence et al, 2001;Schilling et al, 2007;Waelter et al, 2001), mutant superoxide dismutase 1, for modeling familial amyotrophic lateral sclerosis (Karch and Borchelt, 2008;Prudencio et al, 2009;Wang et al, 2003), α-synuclein, for modeling Parkinson's disease (Paxinou et al, 2001), and tau to model various tauopathies (Mirbaha et al, 2015). In each of these cases, expression of a mutant protein, or in some cases a wild-type (WT) protein, produces aggregate inclusions that resemble structures seen in tissues of humans with the disease and relevant animal models.…”

Section: Identification Of Proteostasis Stress Biomarkers In Hek293 Cmentioning

confidence: 99%

Vulnerability of newly synthesized proteins to proteostasis stress

Pattamatta

Hildago

et al. 2016

Journal of Cell Science

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The capacity of the cell to produce, fold and degrade proteins relies on components of the proteostasis network. Multiple types of insults can impose a burden on this network, causing protein misfolding. Using thermal stress, a classic example of acute proteostatic stress, we demonstrate that ∼5-10% of the soluble cytosolic and nuclear proteome in human HEK293 cells is vulnerable to misfolding when proteostatic function is overwhelmed. Inhibiting new protein synthesis for 30 min prior to heat-shock dramatically reduced the amount of heat-stress induced polyubiquitylation, and reduced the misfolding of proteins identified as vulnerable to thermal stress. Following prior studies in C. elegans in which mutant huntingtin (Q103) expression was shown to cause the secondary misfolding of cytosolic proteins, we also demonstrate that mutant huntingtin causes similar 'secondary' misfolding in human cells. Similar to thermal stress, inhibiting new protein synthesis reduced the impact of mutant huntingtin on proteostatic function. These findings suggest that newly made proteins are vulnerable to misfolding when proteostasis is disrupted by insults such as thermal stress and mutant protein aggregation.

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“…However, it is worth noting that the toxic effects of small aggregates of full-length tau have already been described in AD and other tauopathies (54)(55)(56)(57). Furthermore, these oligomeric forms of tau have been implicated in the propagation of the disease process (56,59). Thus, the presence of tau aggregates could also have some deleterious effects in motor neurons in the context of ALS.…”

Section: Resultsmentioning

confidence: 99%