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by claude@2026-07, 2026-07-03
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This study investigated cellular pathways that prevent rupture of endolysosomal vesicles during intercellular spreading of Tau aggregates. The authors created a C. elegans model by expressing an mCherry-labeled aggregation-prone human Tau fragment (F3ΔK281::mCh) in touch receptor neurons, which caused neurotoxicity and mechanosensory deficits and, upon transmission to receiving hypodermal cells, compromised the endolysosomal system. A genome-wide RNAi screen identified 59 genes required for maintaining endolysosomal integrity, with enrichment for ESCRT, ubiquitin-proteasome, mRNA splicing, and fatty acid metabolism pathways; silencing conserved genes increased seeded Tau aggregation in hiPSC-derived cortical neurons and induced endolysosomal rupture in HEK293T cells. The paper does not explicitly state limitations in the provided text, but it relies on a specific Tau fragment and cross-system validation across C. elegans, hiPSC neurons, and HEK293T cells. This paper does not explicitly discuss endometriosis or adenomyosis; it was included in the corpus via a keyword match in the upstream search index.
Abstract
The spreading of Tau pathology is closely associated with the progression of neurodegeneration and cognitive decline in Alzheimer’s disease and other tauopathies. A key event in this process is the rupture of endolysosomal vesicles following the intercellular transfer of Tau aggregates, releasing the transferred Tau species into the cytosol where they can promote the aggregation of endogenous Tau. However, understanding of the cellular pathways involved in this process remains limited. In this study, we investigated cellular pathways that prevent endolysosomal vesicle rupture. We established a new C. elegans model of Tau spreading by introducing an mCherry-labelled, disease-associated aggregation-prone fragment of human Tau (F3 ΔK281 ::mCh) into the six touch receptor neurons. F3 ΔK281 ::mCh transgenic animals exhibited significant neurotoxicity and mechanosensory deficits due to the accumulation of this Tau fragment. In addition, its intercellular transmission compromised the endolysosomal system in receiving hypodermal cells. Using this model, we conducted an unbiased genome-wide RNAi screen and identified 59 genes critical for maintaining endolysosomal integrity. GO-term analysis revealed an enrichment of genes related to the ESCRT complex, the ubiquitin-proteasome system, mRNA splicing, and fatty acid metabolism. Silencing of selected conserved genes exacerbated seeded Tau aggregation in a human induced pluripotent stem cell (hiPSC)-derived cortical neuron model and triggered endolysosomal rupture in HEK293T cells, confirming the crucial role of endolysosomal damage in seeded Tau aggregation. Overall, this study discovered novel cellular pathways that safeguard endolysosomal integrity. These findings may guide the development of therapeutics that improve endolysosomal integrity to halt the progression of Tau pathology.
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Abstract
The spreading of Tau pathology is closely associated with the progression of neurodegeneration and cognitive decline in Alzheimer’s disease and other tauopathies. A key event in this process is the rupture of endolysosomal vesicles following the intercellular transfer of Tau aggregates, releasing the transferred Tau species into the cytosol where they can promote the aggregation of endogenous Tau. However, understanding of the cellular pathways involved in this process remains limited.
In this study, we investigated cellular pathways that prevent endolysosomal vesicle rupture. We established a new C. elegans model of Tau spreading by introducing an mCherry-labelled, disease-associated aggregation-prone fragment of human Tau (F3ΔK281::mCh) into the six touch receptor neurons. F3ΔK281::mCh transgenic animals exhibited significant neurotoxicity and mechanosensory deficits due to the accumulation of this Tau fragment. In addition, its intercellular transmission compromised the endolysosomal system in receiving hypodermal cells. Using this model, we conducted an unbiased genome-wide RNAi screen and identified 59 genes critical for maintaining endolysosomal integrity. GO-term analysis revealed an enrichment of genes related to the ESCRT complex, the ubiquitin-proteasome system, mRNA splicing, and fatty acid metabolism. Silencing of selected conserved genes exacerbated seeded Tau aggregation in a human induced pluripotent stem cell (hiPSC)-derived cortical neuron model and triggered endolysosomal rupture in HEK293T cells, confirming the crucial role of endolysosomal damage in seeded Tau aggregation.
Overall, this study discovered novel cellular pathways that safeguard endolysosomal integrity. These findings may guide the development of therapeutics that improve endolysosomal integrity to halt the progression of Tau pathology.
Competing Interest Statement
D.C.S., P.R., T.L., J.S.R., L.G. and D.E.E. are employees of AbbVie. A.S. and T.R.J. are former AbbVie employees. The other authors declare no competing interests.
List of Abbreviation
- C. elegans
- Caenorhabditis elegans
- hiPSC
- human induced pluripotent stem cell
- PD
- Parkinson’s disease
- AD
- Alzheimer’s disease
- α-Syn
- SNCA/α-synuclein
- BWM
- body wall muscle
- DA
- dopaminergic
- ALM
- anterior lateral microtubule cell
- AVM
- anterior ventral microtubule cell
- PLM
- posterior lateral microtubule cell
- PVM
- posterior ventral microtubule cell
- sfGFP
- superfolder Green Flourescent Protein
- LGALS3
- galectin-3
- nt-cntrl
- non-targeting siRNA
- rPHFs
- recombinant paired helical filaments
- Tau
- MAPT
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