TauP301L disengages from the proteosome core complex and neurogranin coincident with enhanced neuronal network excitability

• Published in: Cell death & disease Vol. 15; no. 6; pp. 429 - 15
• Main Authors: Hole, Katriona L., Zhu, Bangfu, Huggon, Laura, Brown, Jon T., Mason, Jody M., Williams, Robert J.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 18-06-2024; Springer Nature B.V; Nature Publishing Group
• Subjects: 13; 13/1; 13/106; 13/44; 14/35; 38; 631/378/340; 631/80/86/1999; 82; 82/58; 9/30; Antibodies; Biochemistry; Biomarkers; Biomedical and Life Sciences; Ca2+/calmodulin-dependent protein kinase II; Calcineurin; Calcium signalling; Calmodulin; Cell Biology; Cell Culture; Cell death; Excitability; Glucose; Immunology; Life Sciences; Mass spectrometry; Mass spectroscopy; Neural networks; Neurodegeneration; Neurodegenerative diseases; Neurogranin; Penicillin; Phosphorylation; Plasmids; Proteasomes; Ribosomal proteins; Scientific imaging; Signal transduction; Tau protein
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-024-06815-2

Tauopathies are characterised by the pathological accumulation of misfolded tau. The emerging view is that toxic tau species drive synaptic dysfunction and potentially tau propagation before measurable neurodegeneration is evident, but the underlying molecular events are not well defined. Human non-mutated 0N4R tau (tau
WT
) and P301L mutant 0N4R tau (tau
P301L
) were expressed in mouse primary cortical neurons using adeno-associated viruses to monitor early molecular changes and synaptic function before the onset of neuronal loss. In this model tau
P301L
was differentially phosphorylated relative to tau
wt
with a notable increase in phosphorylation at ser262. Affinity purification - mass spectrometry combined with tandem mass tagging was used to quantitatively compare the tau
WT
and tau
P301L
interactomes. This revealed an enrichment of tau
P301L
with ribosomal proteins but a decreased interaction with the proteasome core complex and reduced tau
P301L
degradation. Differences in the interaction of tau
P301L
with members of a key synaptic calcium-calmodulin signalling pathway were also identified, most notably, increased association with CaMKII but reduced association with calcineurin and the candidate AD biomarker neurogranin. Decreased association of neurogranin to tau
P301L
corresponded with the appearance of enhanced levels of extracellular neurogranin suggestive of potential release or leakage from synapses. Finally, analysis of neuronal network activity using micro-electrode arrays showed that overexpression of tau
P301L
promoted basal hyperexcitability coincident with these changes in the tau interactome and implicating tau in specific early alterations in synaptic function.