Human iPSC 4R tauopathy model uncovers modifiers of tau propagation

Bravo, Concepciòn; Giani, Alice Maria; Madero-Pérez, Jesús; Zhao, Zhongyan; Samelson, Avi J.; Wong, Man Ying; Evangelisti, Alessandro; Fan, Li; Pozner, Tatyana; Mercedes, María; Patel, Tark; Yarahmady, Allan; Carling, Gillian K.; Lee, Virginia M.‐Y.; Sharma, Manu; Mok, Sue-Ann; Luo, Wenjie; Zhao, Mingrui; Kampmann, Martin; Gong, Shiaoching; Gan, Li

doi:10.1101/2023.06.19.544278

Cited by 6 publications

(3 citation statements)

References 82 publications

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“…Consistent with in vivo data, we also observed a significant decrease of proteostasis gene expression as well as an increase of YAP1-TEAD2 target gene expression in human induced pluripotent stem cells (iPSC)-derived neurons that express the P301S 4R-Tau when compared to wild-type 4R-Tau control cells (Fig. 6a-c) 73 . These upregulated YAP1-TEAD2 target genes also overlap with those repressed by PP (Fig.…”

Section: Pp Has the Potential For Treating Tauopathy In Humanssupporting

confidence: 89%

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SON-dependent nuclear speckle rejuvenation alleviates proteinopathies

Dion,

Tao,

Chambers

et al. 2024

Preprint

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Current treatments targeting individual protein quality control have limited efficacy in alleviating proteinopathies, highlighting the prerequisite for a common upstream druggable target capable of global proteostasis modulation. Building on our prior research establishing nuclear speckles as pivotal organelles responsible for global proteostasis transcriptional control, we aim to alleviate proteinopathies through nuclear speckle rejuvenation. We identified pyrvinium pamoate as a small-molecule nuclear speckle rejuvenator that enhances protein quality control while suppressing YAP1 signaling via decreasing the surface tension of nuclear speckle condensates through interaction with the intrinsically disordered region of nuclear speckle scaffold protein SON. In pre-clinical models, pyrvinium pamoate reduced tauopathy and alleviated retina degeneration by promoting autophagy and ubiquitin-proteasome system. Aberrant nuclear speckle morphology, reduced protein quality control and increased YAP1 activity were also observed in human tauopathies. Our study uncovers novel therapeutic targets for tackling protein misfolding disorders within an expanded proteostasis framework encompassing nuclear speckles and YAP1.

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Section: Pp Has the Potential For Treating Tauopathy In Humanssupporting

confidence: 89%

“…Both UPS and ALP are involved in the degradation of tau protein in tauopathies [70][71][72][73] . To test the effect of PP on tau proteostasis in mouse primary neuronal cultures, we overexpressed human Tau carrying P301S mutation -an FTD-causing mutation in the human MAPT gene (Tau) 74 .…”

Section: Pp Reduces Both Pathological Tau and Rhodopsin Levels By Boo...mentioning

confidence: 99%

SON-dependent nuclear speckle rejuvenation alleviates proteinopathies

Dion,

Tao,

Chambers

et al. 2024

Preprint

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“…Several recent studies have linked UFM1 and USP19 to the intercellular transfer of neurodegenerative disease-associated neurotoxic proteins. Specifically, in UFM1-deficient induced pluripotent stem cell-derived neurons and in USP19 KO mice, the seeding and propagation of misfolded Tau and α-Syn are inhibited (45)(46)(47). Although the underlying mechanisms are unclear, these studies and our work consolidate an emerging theme that the dynamics of protein aggregation may be influenced by a functional interplay between USP19 and UFM1 in either MAPS or a related UcPS process.…”

Section: Discussionsupporting

confidence: 55%

Mono-UFMylation promotes misfolding-associated secretion of α-synuclein

Wang,

Xu,

Fukushige

et al. 2024

Sci. Adv.

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Stressed cells secret misfolded proteins lacking signaling sequence via an unconventional protein secretion (UcPS) pathway, but how misfolded proteins are targeted selectively in UcPS is unclear. Here, we report that misfolded UcPS clients are subject to modification by a ubiquitin-like protein named ubiquitin-fold modifier 1 (UFM1). Using α-synuclein (α-Syn) as a UcPS model, we show that mutating the UFMylation sites in α-Syn or genetic inhibition of the UFMylation system mitigates α-Syn secretion, whereas overexpression of UFBP1, a component of the endoplasmic reticulum–associated UFMylation ligase complex, augments α-Syn secretion in mammalian cells and in model organisms. UFM1 itself is cosecreted with α-Syn, and the serum UFM1 level correlates with that of α-Syn. Because UFM1 can be directly recognized by ubiquitin specific peptidase 19 (USP19), a previously established UcPS stimulator known to associate with several chaperoning activities, UFMylation might facilitate substrate engagement by USP19, allowing stringent and regulated selection of misfolded proteins for secretion and proteotoxic stress alleviation.

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The six brain‐specific TAU isoforms and their role in Alzheimer's disease and related neurodegenerative dementia syndromes

Buchholz,

Zempel

2024

Alzheimer's & Dementia

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INTRODUCTIONAlternative splicing of the human MAPT gene generates six brain‐specific TAU isoforms. Imbalances in the TAU isoform ratio can lead to neurodegenerative diseases, underscoring the need for precise control over TAU isoform balance. Tauopathies, characterized by intracellular aggregates of hyperphosphorylated TAU, exhibit extensive neurodegeneration and can be classified by the TAU isoforms present in pathological accumulations.METHODSA comprehensive review of TAU and related dementia syndromes literature was conducted using PubMed, Google Scholar, and preprint server.RESULTSWhile TAU is recognized as key driver of neurodegeneration in specific tauopathies, the contribution of the isoforms to neuronal function and disease development remains largely elusive.DISCUSSIONIn this review we describe the role of TAU isoforms in health and disease, and stress the importance of comprehending and studying TAU isoforms in both, physiological and pathological context, in order to develop targeted therapeutic interventions for TAU‐associated diseases.Highlights MAPT splicing is tightly regulated during neuronal maturation and throughout life. TAU isoform expression is development‐, cell‐type and brain region specific. The contribution of TAU to neurodegeneration might be isoform‐specific. Ineffective TAU‐based therapies highlight the need for specific targeting strategies.

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Human iPSC 4R tauopathy model uncovers modifiers of tau propagation

Cited by 6 publications

References 82 publications

SON-dependent nuclear speckle rejuvenation alleviates proteinopathies

SON-dependent nuclear speckle rejuvenation alleviates proteinopathies

Mono-UFMylation promotes misfolding-associated secretion of α-synuclein

The six brain‐specific TAU isoforms and their role in Alzheimer's disease and related neurodegenerative dementia syndromes

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