Tauopathy induced by low level expression of a human brain-derived tau fragment in mice is rescued by phenylbutyrate

Bondulich, Marie K.; Guo, Tong; Meehan, Christopher; Manion, John; Martin, T. Rodriguez; Mitchell, Jacqueline C.; Hortobágyi, Tibor; Yankova, Natalia; Stygelbout, Virginie; Brion, Jean Pierre; Noble, Wendy; Hanger, Diane P.

doi:10.1093/brain/aww137

Cited by 51 publications

(80 citation statements)

References 83 publications

(102 reference statements)

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“…43 Tau cleaved at both its N- and C-termini has been detected in AD brain. 44 Currently, no consensus exists on whether intact, N-terminally or C-terminally truncated tau is the species of tau that propagates.…”

Section: Resultsmentioning

confidence: 99%

Membrane association and release of wild-type and pathological tau from organotypic brain slice cultures

et al. 2017

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The spatiotemporal transmission of pathological tau in the brain is characteristic of Alzheimer's disease. Release of both soluble and abnormal tau species from healthy neurons is increased upon stimulation of neuronal activity. It is not yet understood whether the mechanisms controlling soluble tau release from healthy neurons is the same as those involved in the spread of pathological tau species. To begin to understand these events, we have studied tau distribution and release using organotypic brain slice cultures. The slices were cultured from postnatal wild-type and 3xTg-AD mice for up to 1 month. Tau distribution in subcellular compartments was examined by western blotting, and tau release into culture medium was determined using a sensitive sandwich ELISA. We show here that 3xTg-AD cultures have an accelerated development of pathological tau abnormalities including the redistribution of tau to synaptic and membrane compartments. The 3xTg-AD slice cultures show elevated basal tau release relative to total tau when compared with wild-type cultures. However, tau release from 3xTg-AD slices cannot be further stimulated when neuronal activity is increased with potassium chloride. Moreover, we report that there is an increased pool of dephosphorylated membrane-associated tau in conditions where tau release is increased. These data suggest that there may be differential patterns of tau release when using integrated slice culture models of wild-type and transgenic mouse brain, although it will be important to determine the effect of tau overexpression for these findings. These results further increase our knowledge of the molecular mechanisms underlying tau release and propagation in neurodegenerative tauopathies.

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Section: Resultsmentioning

confidence: 99%

Membrane association and release of wild-type and pathological tau from organotypic brain slice cultures

et al. 2017

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“…A growing body of evidence demonstrates the distinct property of 4-PBA to restore trafficking of misfolded proteins and to mitigate ER stress in a range of in vitro systems, and in animal models of metabolic and neurodegenerative diseases (Bondulich et al, 2016; Ozcan et al, 2006; Rubenstein et al, 1997). By establishing that 4-PBA acts on the COPII sorting machinery to attenuate ER retention, our findings should be an invaluable aid to proof of principle studies involving 4-PBA and its analogs.…”

Section: Resultsmentioning

confidence: 99%

ER retention is imposed by COPII protein sorting and attenuated by 4-phenylbutyrate

Goldberg

2017

eLife

102

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Native cargo proteins exit the endoplasmic reticulum (ER) in COPII-coated vesicles, whereas resident and misfolded proteins are substantially excluded from vesicles by a retention mechanism that remains unresolved. We probed the ER retention process using the proteostasis regulator 4-phenylbutyrate (4-PBA), which we show targets COPII protein to reduce the stringency of retention. 4-PBA competes with p24 proteins to bind COPII. When p24 protein uptake is blocked, COPII vesicles package resident proteins and an ER-trapped mutant LDL receptor. We further show that 4-PBA triggers the secretion of a KDEL-tagged luminal resident, implying that a compromised retention mechanism causes saturation of the KDEL retrieval system. The results indicate that stringent ER retention requires the COPII coat machinery to actively sort biosynthetic cargo from diffusible misfolded and resident ER proteins.DOI: http://dx.doi.org/10.7554/eLife.26624.001

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“…Improved cognitive performance. Bondulich et al, 2016Cuadrado-Tejedor et al, 2013. Ricobaraza et al, 2009+2012 Wiley et al, 2011Zhang et al, 2016 TUDCA Chemically induced UPR -Reduced apoptotic cell death.…”

Section: Likely Indirect Promotion Of Protein Chaperone Handlingmentioning

confidence: 99%

Alzheimer’s disease pathology and the unfolded protein response: prospective pathways and therapeutic targets

Koss

Platt

2017

Behavioural Pharmacology

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Many vital interdependent cellular functions including proteostasis, lipogenesis and Ca homeostasis are executed by the endoplasmic reticulum (ER). Exogenous insults can impair ER performance: this must be rapidly corrected or cell death will ensue. Protective adaptations can boost the functional capacity of the ER and form the basis of the unfolded protein response (UPR). Activated in response to the accumulation of misfolded proteins, the UPR can halt protein translation while increasing protein-handling chaperones and the degradation of erroneous proteins through a conserved three-tier molecular cascade. However, prolonged activation of the UPR can result in the maladaptation of the system, resulting in the activation of inflammatory and apoptotic effectors. Recently, UPR and its involvement in neurodegenerative disease has attracted much interest and numerous potentially 'drugable' points of crosstalk are now emerging. Here, we summarize the functions of the ER and UPR, and highlight evidence for its potential role in the pathogenesis of Alzheimer's disease, before discussing several key targets with therapeutic potential.

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Tauopathy induced by low level expression of a human brain-derived tau fragment in mice is rescued by phenylbutyrate

Cited by 51 publications

References 83 publications

Membrane association and release of wild-type and pathological tau from organotypic brain slice cultures

Membrane association and release of wild-type and pathological tau from organotypic brain slice cultures

ER retention is imposed by COPII protein sorting and attenuated by 4-phenylbutyrate

Alzheimer’s disease pathology and the unfolded protein response: prospective pathways and therapeutic targets

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