Abstract
The risk of developing tauopathic neurodegenerative disease depends in part on the levels and composition of six naturally occurring Tau isoforms in human brain. These proteins, which form filamentous aggregates in disease, vary only by the presence or absence of three inserts encoded by alternatively spliced exons 2, 3, and 10 of the Tau gene (MAPT). To determine the contribution of alternatively spliced segments to Tau aggregation propensity, the aggregation kinetics of six unmodified, recombinant human Tau isoforms were examined in vitro using electron microscopy assay methods. Aggregation propensity was then compared at the level of elementary rate constants for nucleation and extension phases. We found that all three alternatively spliced segments modulated Tau aggregation but through differing kinetic mechanisms that could synergize or compete depending on sequence context. Overall, segments encoded by exons 2 and 10 promoted aggregation, whereas the segment encoded by exon 3 depressed it with its efficacy dependent on the presence or absence of a fourth microtubule binding repeat. In general, aggregation propensity correlated with genetic risk reported for multiple tauopathies, implicating aggregation as one candidate mechanism rationalizing the correlation between Tau expression patterns and disease.
Highlights
Human brain Tau isoforms differ by the presence or absence of inserts derived from alternative splicing of MAPT transcripts
At equimolar and low (1:3) 4R:3R ratios, Kcrit shifted to a value intermediate between the fully dominant and non-interacting scenarios. These data indicate that the high aggregation propensity of 4R Tau can be partially dominant over 3R Tau, suggesting that the 4R species can recruit less assembly prone Tau isoforms into aggregates in the submicromolar free Tau concentration regime. These data show that the intrinsic aggregation propensity of naturally occurring, unmodified human Tau isoforms differs owing to the contributions of N- and C-terminal inserts to the nucleation and extension steps of the aggregation pathway (Fig. 6)
The Tau isoform lacking all three inserts, 0N3R, aggregates with a slow nucleation rate and relatively high Kcrit. Consistent with this finding, human fetal Tau, which consists of 0N3R Tau [41], is not associated with aggregation despite being hyperphosphorylated during development [42]
Summary
Human brain Tau isoforms differ by the presence or absence of inserts derived from alternative splicing of MAPT transcripts. Results: Tau inserts modulate Tau aggregation propensity through differing kinetic mechanisms that synergize or compete depending on sequence context. The risk of developing tauopathic neurodegenerative disease depends in part on the levels and composition of six naturally occurring Tau isoforms in human brain. These proteins, which form filamentous aggregates in disease, vary only by the presence or absence of three inserts encoded by alternatively spliced exons 2, 3, and 10 of the Tau gene (MAPT). We found that all three alternatively spliced segments modulated Tau aggregation but through differing kinetic mechanisms that could synergize or compete depending on sequence context. Aggregation propensity correlated with genetic risk reported for multiple tauopathies, implicating aggregation as one candidate mechanism rationalizing the correlation between Tau expression patterns and disease
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
