Leaky endosomes push tau over the seed limit

Ugbode, Chris; Fort-Aznar, Laura; Sweeney, Sean T.

doi:10.1074/jbc.h119.011687

Cited by 6 publications

(3 citation statements)

References 10 publications

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“…Once brought into the cell via endocytosis, exogenous tau must somehow exit the vesicle lumen to serve as a template for conversion of endogenous tau monomer in the cytoplasm. The mechanisms by which this occurs are unknown, and could include vesicle rupture (Falcon et al, 2018; Soares et al, 2021; Ugbode et al, 2019), although our recent work suggests this is not required (Kolay et al, 2022). We have developed methods to quantify tau uptake using flow cytometry (Holmes et al, 2013), and to measure induction of intracellular aggregation based on fluorescence resonance energy transfer (FRET) in engineered “biosensor” cell lines (Holmes et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Tau seeds translocate across the cell membrane to initiate aggregation

Dodd

LaCroix

Valdez

et al. 2022

Preprint

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Neurodegenerative tauopathies, including Alzheimer’s disease and related disorders, are caused by intracellular aggregation of tau protein in ordered assemblies. Experimental evidence suggests that tau assemblies propagate pathology across brain networks. Tau seeds enter cells through endocytosis but must access the cytoplasm to serve as templates for their own replication. The mechanism by which this occurs is unknown. To study tau uptake, we began with a whole-genome CRISPR knockout screen, which indicated a requirement vacuolar H+ ATPase (v-ATPase) components. Treatment with Bafilomycin A1, an inhibitor of the v-ATPase, also reduced tau entry. We next tested direct modifiers of endolysosomal trafficking. Dominant-negative Rab5a expression uniquely decreased tau uptake, as did temporary cold temperature during tau exposure, consistent with a primary role of endocytosis in tau uptake. However, despite reducing tau uptake, these interventions all paradoxically increased intracellular seeding. Consequently, we generated giant plasma membrane vesicles (GPMVs), which cannot undergo endocytosis, and observed that tau fibrils and monomer translocated into the vesicles, in addition to TAT peptide, whereas transferrin and albumin did not. In every case, tau required binding to heparan sulfate proteoglycans (HSPGs) for cell uptake, seeding, or GPMV entry. These findings are most consistent with direct translocation of tau seeds across the lipid bilayer, a novel mechanism of entry into the cytoplasm.

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Section: Introductionmentioning

confidence: 99%

Tau seeds translocate across the cell membrane to initiate aggregation

Dodd

LaCroix

Valdez

et al. 2022

Preprint

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“…In a forward genetic screen aimed at identifying Rabs that regulate phagocytic processing of neuronal mHTT ex1 aggregates, we uncovered glial Rab10 as a modifier of prion-like spreading of mHTT ex1 from neurons to glia. Interestingly, several other Rab proteins have been previously reported to alter secretion or cell-to-cell propagation of tau or α-synuclein aggregates (Rodriguez et al, 2017; Bae et al, 2018; Ugbode et al, 2019; Rodrigues et al, 2022), suggesting that Rab-dependent processes could be a common mechanism underlying prion-like diseases. Our data suggest that Rab10 acts downstream of Draper to enable engulfed mHTT ex1 aggregates to evade lysosomal degradation, perhaps escaping to the cytoplasm during Rab10-dependent intracellular membrane fusion.…”

Section: Discussionmentioning

confidence: 99%

Impairment of the glial phagolysosomal system drives prion-like propagation in aDrosophilamodel of Huntington’s disease

Davis,

Zaya,

Panning Pearce

2023

Preprint

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Amyloid aggregate accumulation and spread between synaptically-connected regions of the brain is a hallmark of neurodegenerative disease progression. Glia participate in neuropathogenesis by reducing protein aggregate loads via phagocytosis while simultaneously acting as vectors for aggregate spread between cells. Emerging evidence supports the hypothesis that aggregate accumulation compromises the ability of glia to clear toxic material from the brain, possibly by disrupting the phagolysosomal compartment. A better understanding of how glia become deficient in the disease state could reveal novel therapeutic targets. Here, we report that mutant huntingtin (mHTT) aggregates impair glial responsiveness to injury and capacity to degrade axonal debris in aDrosophilamodel of Huntington’s disease (HD). mHTT aggregate formation in neurons slowed engulfment and clearance of injured axons and caused accumulation of late phagosomes and lysosomes in glia. Neuronal mHTT expression induced innate immunity and phagocytic genes, some of which regulated mHTT aggregate burden in the brain. A forward genetic screen targeting glial Rab GTPases revealed Rab10 as a novel modifier of mHTT aggregate transmission from neurons to glia that acts downstream of the phagocytic receptor, Draper. This suggests that Rab-mediated intercellular vesicle sorting mechanisms could create opportunities for prion-like mHTT aggregates to escape lysosomal degradation. Together, our findings support a model in which mHTT aggregate build-up within the phagolysosomal system impairs glial phagocytosis while also promoting the generation of seeding-competent pathological proteins. The new mechanistic information we report here adds to a growing recognition of phagocytic glia as double-edged players in prion-like proteopathies such as HD.SIGNIFICANCE STATEMENTDeposition of amyloid aggregates is closely associated with neurodegenerative disease progression and neuronal death. Recent studies highlight glia as dynamic mediators of disease, capable of phagocytosing dying neurons and amyloid aggregates, while also inducing chronic inflammation and promoting proteopathic spread. Thus, glia have emerged as promising therapeutic targets for disease intervention. Here, we demonstrate in aDrosophilamodel of Huntington’s disease that neuronal mHTT aggregates interfere with glial phagocytic functions, stimulate innate immunity signaling, and impair phagolysosomal processing. We also identify Rab10 as a novel modifier of prion-like transmission of mHTT aggregates, suggesting that Rab-mediated intramembrane fusion in the phagolysosomal system could drive aggregate pathology spread.

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“…First, we do not know how pathogenic Tau seeds affect exosome biogenesis during AD ( Figure 2 ). Chen et al recently observed that Tau is readily taken up into the cell via endocytosis, followed by release into the cytosol when the endolysosomal system was compromised, where propagation of tau aggregation occurred [ 116 ]. Yan et al revealed that increased exosome release counteracts endolysosomal dysfunction of Tau processing but increases the number of aggregates and the propagation of Tau [ 117 ].…”

Section: Tauopathy Seeding and Its Spread In The Ds Brainmentioning

confidence: 99%

The Role of Tau Pathology in Alzheimer’s Disease and Down Syndrome

Granholm,

Hamlett

2024

JCM

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Background: Individuals with Down syndrome (DS) exhibit an almost complete penetrance of Alzheimer’s disease (AD) pathology but are underrepresented in clinical trials for AD. The Tau protein is associated with microtubule function in the neuron and is crucial for normal axonal transport. In several different neurodegenerative disorders, Tau misfolding leads to hyper-phosphorylation of Tau (p-Tau), which may seed pathology to bystander cells and spread. This review is focused on current findings regarding p-Tau and its potential to seed pathology as a “prion-like” spreader. It also considers the consequences of p-Tau pathology leading to AD, particularly in individuals with Down syndrome. Methods: Scopus (SC) and PubMed (PM) were searched in English using keywords “tau AND seeding AND brain AND down syndrome”. A total of 558 SC or 529 PM potentially relevant articles were identified, of which only six SC or three PM articles mentioned Down syndrome. This review was built upon the literature and the recent findings of our group and others. Results: Misfolded p-Tau isoforms are seeding competent and may be responsible for spreading AD pathology. Conclusions: This review demonstrates recent work focused on understanding the role of neurofibrillary tangles and monomeric/oligomeric Tau in the prion-like spreading of Tau pathology in the human brain.

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Leaky endosomes push tau over the seed limit

Abstract: york.ac.uk. 2 The abbreviations used are: AD, Alzheimer's disease; FTD, familial frontotemporal dementia; ESCRT, endosomal sorting complex required for transport; MVB, multivesicular body; CRISPRi, CRISPR interference. EDITORS' PICK HIGHLIGHT

Cited by 6 publications

References 10 publications

Tau seeds translocate across the cell membrane to initiate aggregation

Tau seeds translocate across the cell membrane to initiate aggregation

Impairment of the glial phagolysosomal system drives prion-like propagation in aDrosophilamodel of Huntington’s disease

The Role of Tau Pathology in Alzheimer’s Disease and Down Syndrome

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