Protein with Tau-like repeats (PTL-1) is the sole Tau /MAP2/MAP4 homolog in Caenorhabditis elegans. Dysregulation of Tau is a pathological hallmark of neurodegenerative diseases such as Alzheimer’s disease. Therefore, reducing Tau levels has been suggested as a therapeutic strategy.
We used PTL-1 to model the biological functions of a Tau-like protein without the complication of functional redundancy. Firstly, our data indicate that PTL-1 in the nervous system mediates the oxidative stress response in a pathway that may involve the C. elegans homolog of the Nrf2 transcription factor, SKN-1. In addition, we found that ptl-1 mutant animals are short-lived, and that lifespan modulation by PTL-1 may occur via similar processes to those mediated by SKN-1. We also observed that the short-lived phenotype of ptl-1 mutants can be rescued by transgenic re-expression of PTL-1 but not human Tau. Secondly, we show that PTL-1 maintains the structural integrity of neurons with increasing age. This phenotype observed in ptl-1 mutant animals could again be rescued by PTL-1 re-expression but not by human Tau. Thirdly, our data also indicate that the regulation of neuronal ageing by PTL-1 is cell-autonomous. We expressed PTL-1 in touch neurons and showed rescue of the neuronal ageing phenotype of ptl-1 mutant animals in these neurons but not in another neuronal subset. Knockdown of PTL-1 specifically in
touch neurons also resulted in premature neuronal ageing in these neurons but not in a distinct subset of neurons, further supporting the conclusion that PTL-1 functions in a cell-autonomous manner. Interestingly, we showed that expression of PTL-1 in touch neurons alone was unable to rescue the shortened lifespan observed in null mutants, indicating that premature neuronal ageing in touch neurons and organismal ageing can be decoupled.
Our data show that PTL-1 in C. elegans is a useful model to investigate the physiological
functions of a Tau-like protein. Overall, our findings that PTL-1 is involved in the stress
response, neuronal ageing and lifespan modulation suggest that some of the effects of Tau
pathology may result from the loss of physiological Tau functions and not solely from a toxic
gain-of-function due to an accumulation of Tau.