Tunable Tau Expression in C. elegans Neurons Reveals that Early-AD Tau Phosphorylation Selectively Impacts Behavior and Mitochondrial Quality Control

Tau protein accumulates myriad post-translational modifications as Alzheimers disease (AD) progresses, and early-disease tau modifications such as phosphorylation at threonine 231 (T231) likely play a key role in AD pathogenesis. Here, a series of "tunable tau" strains was developed in C. elegans to test the relative impact of tau pseudo-phosphorylation of T231 (T231E) compared to protein expression level as a driver of phenotypic penetrance and severity. Multiple copies of a cassette coding for pan-neuronal wildtype tau or T231E were inserted at a genomic safe harbor loci to create a repertoire of strains expressing tau from low to high levels. In stereotypical behavioral assays of locomotory activity, T231E selectively impacted phenotypic severity compared to wild-type human tau controls, which further tracked with age and tau expression level. However, deficits in associative memory were non-selective between tau and T231E. Moreover, genetic, pharmacologic, and molecular approaches indicated that mitophagy modulation could suppress T231E phenotypes. Additionally, a robust mitochondrial unfolded protein response (UPRmt) occurred in T231E, and loss of atfs-1, a transcription factor central to the UPRmt suppressed T231E toxicity. These results demonstrate that phenotypic severity is invariably associated with tau dosage, while early-AD relevant modifications can be causative drivers of selective deficits. Consistent with recent findings, enhancing mitophagy or suppressing potentially maladaptive consequences of persistent UPRmt induction can be beneficial. This provides a solid foundation for further interrogation into mitochondrial quality control disruption as a potential root cause for AD pathogenesis. HighlightsO_LIMatched sets of pan-neuronal, multi-copy tau strains enhance experimental control C_LIO_LIPhosphomimetic tau elicits selective behavioral and neuronal dysfunction C_LIO_LIPhosphomimetic tau triggers a unique mitochondrial unfolded response C_LIO_LITau depletion and mitochondrial interventions rescue observed deficits C_LI Visual Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=168 SRC="FIGDIR/small/701793v1_ufig1.gif" ALT="Figure 1"> View larger version (37K): org.highwire.dtl.DTLVardef@c5afb3org.highwire.dtl.DTLVardef@921b6corg.highwire.dtl.DTLVardef@466f8borg.highwire.dtl.DTLVardef@45452f_HPS_FORMAT_FIGEXP M_FIG C_FIG