Improving Mouse Models for Dementia. Are All the Effects in Tau Mouse Models Due to Overexpression?

Joel, Zelah; Izquierdo, Pablo; Salih, Dervis A.; Richardson, Jill C.; Cummings, Damian M.; Edwards, Frances A.

doi:10.1101/sqb.2018.83.037531

Cited by 11 publications

(11 citation statements)

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“…Rob Malenka showed that activating serotonergic dorsal raphe neurons could reverse social deficits in the 16p11.2 model (Klawonn and Malenka 2019), and Pico Caroni showed how the plasticity of inhibitory neurons underlies specific learning processes and reported that in 22q11 deletion syndrome model mice, D2 receptor antagonists transiently rescue baseline and activation-induced parvalbumin plasticity in adult mice. Frances Edwards discussed improved transgenic mouse models of Alzheimer's disease that avoid the problems of overexpression models (Joel et al 2019). These talks highlighted how it is possible to track down the molecular mechanisms and circuit impact of genetic insults and, in some cases, identify ways to rescue the resulting behavioral deficits.…”

Section: Curiosity-driven Science Connects With the Clinicmentioning

confidence: 99%

Summary: Order and Disorder in Brains and Behavior

Kepecs

2018

Cold Spring Harb Symp Quant Biol

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System explored the tremendous recent progress in neuroscience and how these advances may be used to improve brain health and address psychiatric and neurological disorders. The Symposium explored a vast array of topics from cell types to cognition. My summary focuses on a few emerging themes. Innovative techniques were ever-present, opening up new experimental possibilities. The commoditization of many state-of-the-art technologies is pushing neuroscience beyond its artisanal ways. Another important theme was "circuits in the middle": Numerous presentations dissected cell type-specific circuits that connect different levels of analysis from molecules to behavior. These new technologies have enabled curiosity-driven investigations in animals to connect more directly with preclinical and clinical studies of human brain disorders. Numerous emerging approaches were presented in human neuroscience, bolstering the hope that circuit-specific manipulations will soon provide improved treatments for brain disorders.The seat of the soul and the control of voluntary movement-in fact, of nervous functions in general-are to be sought in the heart. The brain is an organ of minor importance… .-Aristotle, De motu animalium

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Section: Curiosity-driven Science Connects With the Clinicmentioning

confidence: 99%

Summary: Order and Disorder in Brains and Behavior

Kepecs

2018

Cold Spring Harb Symp Quant Biol

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“…5A, hi-TAU, low-TAU). Moreover, tau was detected in NFTs in hi-TAU mice reflecting the severe tau pathology in these animals at 12 months with a less severe pathology in the low-TAU mice of the same age as indicated by fewer NFTs [18].…”

Section: Nub1 Co-localizes With Phosphorylated Tau P62 and Lamp1 In mentioning

confidence: 91%

“…We investigated the localization of endogenous NUB1 and tau in the hippocampus of wild type and TAU mice expressing P301L tau (0N4R) [17,18] (Fig. 5 and S3).…”

Section: Nub1 Co-localizes With Phosphorylated Tau P62 and Lamp1 In mentioning

confidence: 99%

“…The TAU mouse is a model of tauopathy that encodes the 0N4R isoform of human microtubule-associated tau (MAPT) containing the P301L mutation, that causes frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), and was generated by GSK. Hi-TAU mice have approximately 10 copies of the transgene, about twice the copy number of low-TAU mice [17,18]. The expression of P301L mutant tau is driven by the CaMKII promoter heterozygously expressed on a C57BL/6j background [17,18].…”

Section: Animalsmentioning

confidence: 99%

“…Hi-TAU mice have approximately 10 copies of the transgene, about twice the copy number of low-TAU mice [17,18]. The expression of P301L mutant tau is driven by the CaMKII promoter heterozygously expressed on a C57BL/6j background [17,18].…”

Section: Animalsmentioning

confidence: 99%

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Negative Regulator of Ubiquitin-Like Protein 1 modulates the autophagy–lysosomal pathway via p62 to facilitate the extracellular release of tau following proteasome impairment

Guarascio¹,

Salih²,

Yasvoina³

et al. 2019

Human Molecular Genetics

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Negative regulator of ubiquitin-like protein 1 (NUB1) and its longer isoform NUB1L are ubiquitin-like (UBL)/ubiquitin-associated (UBA) proteins that facilitate the targeting of proteasomal substrates, including tau, synphilin-1 and huntingtin. Previous data revealed that NUB1 also mediated a reduction in tau phosphorylation and aggregation following proteasome inhibition, suggesting a switch in NUB1 function from targeted proteasomal degradation to a role in autophagy. Here, we delineate the mechanisms of this switch and show that NUB1 interacted specifically with p62 and induced an increase in p62 levels in a manner facilitated by inhibition of the proteasome. NUB1 moreover increased autophagosomes and the recruitment of lysosomes to aggresomes following proteasome inhibition. Autophagy flux assays revealed that NUB1 affected the autophagy–lysosomal pathway primarily via the UBA domain. NUB1 localized to cytosolic inclusions with pathological forms of tau, as well as LAMP1 and p62 in the hippocampal neurons of tauopathy mice. Finally, NUB1 facilitated the extracellular release of tau following proteasome inhibition. This study thus shows that NUB1 plays a role in regulating the autophagy–lysosomal pathway when the ubiquitin proteasome system is compromised, thus contributing to the mechanisms targeting the removal of aggregation-prone proteins upon proteasomal impairment.

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