Tau interactome maps synaptic and mitochondrial processes associated with neurodegeneration.
Cell
; 185(4): 712-728.e14, 2022 02 17.
Article
in En
| MEDLINE
| ID: mdl-35063084
Tau (MAPT) drives neuronal dysfunction in Alzheimer disease (AD) and other tauopathies. To dissect the underlying mechanisms, we combined an engineered ascorbic acid peroxidase (APEX) approach with quantitative affinity purification mass spectrometry (AP-MS) followed by proximity ligation assay (PLA) to characterize Tau interactomes modified by neuronal activity and mutations that cause frontotemporal dementia (FTD) in human induced pluripotent stem cell (iPSC)-derived neurons. We established interactions of Tau with presynaptic vesicle proteins during activity-dependent Tau secretion and mapped the Tau-binding sites to the cytosolic domains of integral synaptic vesicle proteins. We showed that FTD mutations impair bioenergetics and markedly diminished Tau's interaction with mitochondria proteins, which were downregulated in AD brains of multiple cohorts and correlated with disease severity. These multimodal and dynamic Tau interactomes with exquisite spatial resolution shed light on Tau's role in neuronal function and disease and highlight potential therapeutic targets to block Tau-mediated pathogenesis.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Synapses
/
Tau Proteins
/
Protein Interaction Maps
/
Mitochondria
/
Nerve Degeneration
Type of study:
Risk_factors_studies
Limits:
Humans
Language:
En
Journal:
Cell
Year:
2022
Document type:
Article
Country of publication: