Tau 6D and 6P isoforms inhibit polymerization of full-length tau in vitro.
Alzheimer's disease and other tauopathies are characterized by the intracellular accumulation of insoluble filaments of the microtubule-associated protein tau. The six canonical tau isoforms in the adult brain consist of an N-terminal "projection" domain followed by a proline-rich region, a microtubule-binding repeat region, and a C-terminal tail. However, alternative splicing in exon 6 produces an additional set of tau isoforms, termed 6D and 6P, which contain only the N-terminus and part of the proline-rich region. We have previously shown that constructs representing N-terminal fragments of tau, which resemble the naturally occurring 6P and 6D isoforms, inhibit polymerization of the full-length protein in an in vitro filament formation assay and traced the inhibitory activity to amino acids 18-42. Here we report that 6P and 6D tau isoforms inhibit polymerization of full-length tau (hTau40) in a similar manner, likely by stabilizing full-length tau in a soluble conformation. The absence of exons 2 and 3 decreased the effectiveness of the 6D isoforms but not the 6P variants or the N-terminal tau fragments from our previous study, indicating that the 18-42 region is not the sole determinant of inhibitory ability. Finally, this paper demonstrates that inhibition is blocked by pseudophosphorylation of tyrosines 18 and 29, providing a potential link between tyrosine phosphorylation and disease progression. Taken together, these results indicate that the 6P/6D isoforms are potential endogenous inhibitors of tau filament formation and suggest a mechanism by which this ability may be disrupted in disease.
Lapointe
Nichole E
NE
Department of Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, 60611, USA. lapointe@lifesci.ucsb.edu
Horowitz
Peleg M
PM
Guillozet-Bongaarts
Angela L
AL
Silva
Andres
A
Andreadis
Athena
A
Binder
Lester I
LI
D017398:Alternative Splicing; D000595:Amino Acid Sequence; D006801:Humans; D008969:Molecular Sequence Data; D017510:Protein Folding; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D016875:tau Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
D020033:Protein Isoforms; D016875:tau Proteins