Regulation of age-related structural integrity in neurons by protein with tau-like repeats (PTL-1) is cell autonomous

Abstract

PTL-1 is the sole homolog of the MAP2/MAP4/tau family in Caenorhabditis elegans. Accumulation 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 previously showed that PTL-1 maintains age-related structural integrity in neurons, implying that excessive reduction in the levels of a tau-like protein is detrimental. Here, we demonstrate that the regulation of neuronal ageing by PTL-1 occurs via a cell-autonomous mechanism. We re-expressed PTL-1 in a null mutant background using a pan-neuronal promoter to show that PTL-1 functions in neurons to maintain structural integrity. We next expressed PTL-1 only 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, the ventral nerve cord GABAergic neurons. Knockdown of PTL-1 in touch neurons also resulted in premature neuronal ageing in these neurons but not in GABAergic neurons. Additionally, expression of PTL-1 in touch neurons alone was unable to rescue the shortened lifespan observed in ptl-1 mutants, but pan-neuronal re-expression restored wild-type longevity, indicating that, at least for a specific group of mechanosensory neurons, premature neuronal ageing and organismal ageing can be decoupled.

Neuronal protein with tau‐like repeats (PTL‐1) regulates intestinal SKN‐1 nuclear accumulation in response to oxidative stress

“…We previously showed that PTL-1 regulates neuronal and organismal aging (Chew et al ., 2013 , 2014 ), and now show that it modulates the stress response via SKN-1. Given that tau pathology has also been linked to oxidative stress, our findings provide an interesting avenue for a further investigation into the role of a tau-like protein in stress tolerance and longevity.…”

“…Loss of ptl-1 causes neuronal and organismal aging defects (Chew et al ., 2013 , 2014 ). As aging and stress pathways are intimately linked, we tested whether ptl-1 mutant animals are stress-sensitive.…”

“…We also found that the induction of two other SKN-1 targets, gst-4 ( Park et al ., 2009 ) and hsp-4 (Glover-Cutter et al ., 2013 ), following azide treatment was compromised in ptl-1 mutants and could be rescued by PTL-1 re-expression (Fig S2 ). We previously showed that ptl-1 mutants are short-lived (Chew et al ., 2013 , 2014 ). Others reported that skn-1(zu67), which affects SKN-1a and c, also confers a short-lived phenotype (An et al ., 2003 ).…”

A nematode microtubule-associated protein, PTL-1, closely resembles its mammalian counterparts in overall molecular architecture*

“…Recently, genetic analyses revealed that PTL-1 is involved in neuronal aging, stress responses, and lifespan regulation. [23][24][25] With its limited number of cells that constitute an animal, C. elegans will be useful to determine the sites of MAP actions. The scope of this approach is not restricted to PTL-1 and MAP2/ MAP4/τ, as we hypothesize that all AP-sequence bearing proteins interact with microtubules via similar mechanisms.…”

The molecular mechanism of the Tau-Fyn interaction and dendritic targeting in neurons

“…Mechanistically it has been shown that the mutations reduce microtubule binding and facilitate Tau polymerization [109,110] elegans where the Tau homologue Ptl-1 has been shown to regulate structural neuronal integrity [112,113].…”