Truncated tau interferes with the autophagy and endolysosomal pathway and results in lipid accumulation

The autophagy-lysosomal pathway plays a critical role in the clearance of tau protein aggregates that deposit in the brain in tauopathies, and defects in this system are associated with disease pathogenesis. Here, we report that expression of Tau35, a tauopathy-associated carboxy-terminal fragment o...

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Bibliographic Details
Published in:Cellular and molecular life sciences : CMLS 2024-12, Vol.81 (1), p.304, Article 304
Main Authors: Pollack, Saskia J., Dakkak, Dina, Guo, Tong, Chennell, George, Gomez-Suaga, Patricia, Noble, Wendy, Jimenez-Sanchez, Maria, Hanger, Diane P.
Format: Article
Language:English
Subjects:
Accumulation
Autophagy
Biochemistry
Biomedical and Life Sciences
Biomedicine
Biosynthesis
Cell Biology
Cell lines
Clearances
Dementia
Disease
Electron microscopes
Fatty acids
Life Sciences
Lipids
Neurodegenerative diseases
Neurons
Neurosciences
Nuclear transport
Original
Original Article
Pathogenesis
Proteins
Tau protein
Translocation
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Summary:The autophagy-lysosomal pathway plays a critical role in the clearance of tau protein aggregates that deposit in the brain in tauopathies, and defects in this system are associated with disease pathogenesis. Here, we report that expression of Tau35, a tauopathy-associated carboxy-terminal fragment of tau, leads to lipid accumulation in cell lines and primary cortical neurons. Our findings suggest that this is likely due to a deleterious block of autophagic clearance and lysosomal degradative capacity by Tau35. Notably, upon induction of autophagy by Torin 1, Tau35 inhibited nuclear translocation of transcription factor EB (TFEB), a key regulator of lysosomal biogenesis. Both cell lines and primary cortical neurons expressing Tau35 also exhibited changes in endosomal protein expression. These findings implicate autophagic and endolysosomal dysfunction as key pathological mechanisms through which disease-associated tau fragments could lead to the development and progression of tauopathy.
ISSN:1420-682X
1420-9071
1420-9071
DOI:10.1007/s00018-024-05337-6