Protein with tau-like repeats regulates neuronal integrity and lifespan in<i>C. elegans</i>

Chew, Yee Lian; Fan, Xiaochen; Götz, Jürgen; Nicholas, Hannah R.

doi:10.1242/jcs.jcs124404

Cited by 52 publications

(82 citation statements)

References 63 publications

(103 reference statements)

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“…We visualised GABAergic neuron branching on days 1, 5, 7 and 9 of adulthood using the P unc-47 :: gfp(oxIs12) reporter. As noted previously3457, GABAergic neurons in young animals do not show branching in the dorsally-projecting commissures, which are often branched in older adults (Figure 3a). We found that re-expressing PTL-1 in all neurons in the ptl-1 null mutant background completely rescued premature neuronal ageing observed in ptl-1(ok621) mutant animals (Figure 3b).…”

Section: Resultssupporting

confidence: 79%

“…Specifically, 70% of TRN SID-1 animals fed ptl-1 RNAi bacteria displayed cell body branching at day 7 compared with 47% in the EV RNAi control, and 53% of ptl-1 RNAi-fed animals displayed axon blebbing compared with 30% of the control population (Figure 4ai). In addition, we observed that TRN SID-1 animals displayed a relatively high frequency of axon branching (Figure 4aii), which is normally only present in late stage (day 10) adult animals57. TRN SID-1 animals fed with both control and ptl-1 RNAi treatments showed considerably higher levels of axon branching in the anterior TRNs compared with wild-type controls, although transgenic animals fed ptl-1 bacteria displayed a higher incidence of this phenotype compared with EV treatments (Figure 4ai).…”

Section: Resultsmentioning

confidence: 83%

“…Previously, we demonstrated that re-expressing PTL-1 under the regulation of its endogenous promoter is sufficient to rescue both neuronal ageing and lifespan phenotypes observed in ptl-1 mutant animals7. PTL-1 expression is not restricted to neurons1018; it is also expressed in non-neuronal tissues including vulval cells and stomatointestinal muscle18.…”

Section: Resultsmentioning

confidence: 98%

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

Chew

Fan

Götz

et al. 2014

Sci Rep

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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.

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Section: Resultssupporting

confidence: 79%

Section: Resultsmentioning

confidence: 83%

Section: Resultsmentioning

confidence: 98%

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

Chew

Fan

Götz

et al. 2014

Sci Rep

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“…Tau belongs to the family of microtubule-associated proteins (MAPs), with tau being the prototypical axonal and MAP2 the prototypical dendritic family member [2]. MAPs have a central role in neuronal integrity [3]. While tau has a major function in the axon, early on it was recognized that this protein has also important physiological functions in other compartments, such as the dendrite, where low concentrations of tau facilitate the targeting of the tyrosine-directed kinase Fyn to the dendritic spines [4].…”

mentioning

confidence: 99%

Visualizing the microtubule-associated protein tau in the nucleus

Lü

et al. 2014

Sci. China Life Sci.

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Although tau is mainly known as an axonal microtubule-associated protein, many studies indicate that it is not restricted to this subcellular compartment. Assessing tau's subcellular distribution, however, is not trivial as is evident from transgenic mouse studies. When human tau is over-expressed, it can be immunohistochemically localized to axons and the somatodendritic domain, modeling what is found in neurodegenerative diseases such as Alzheimer's disease. Yet, in wild-type mice, despite its abundance, tau is difficult to visualize even in the axon. It is even more challenging to detect this protein in the nucleus, where tau has been proposed to protect DNA from damage. To establish a framework for future studies into tau's nuclear functions, we compared several methods to visualize endogenous nuclear tau in cell lines and mouse brain. While depending on the fixation and permeabilization protocol, we were able to detect nuclear tau in SH-SY5Y human neuroblastoma cells, we failed to do so in N2a murine neuroblastoma cells. As a second method we used subcellular fractionation of mouse tissue and found that in the nucleus tau is mainly present in a hypophosphorylated form. When either full-length or truncated human tau was expressed, both accumulated in the cytoplasm, but were also found in the nuclear fraction. Because subcellular fractionation methods have their limitations, we finally isolated nuclei to probe for nuclear tau and found that the nuclei were free of cytoplasmic contamination. Together our analysis identifies several protocols for detecting tau in the nucleus where it is found in a less phosphorylated form.

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“…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].…”

Section: Introductionmentioning

confidence: 99%

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

Xia¹

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Alzheimer's disease (AD) is the most common form of neurodegenerative disorder that progresses with aging. The AD brain is characterized by a massive loss of neurons and synapses. Two key hallmarks of AD are the aggregation of the amyloid-β (Aβ) peptide as plaques and of the microtubule-associated protein Tau as neurofibrillary tangles. Under physiological conditions, Tau is mainly localized to the axon of neurons, with low levels of expression found in dendrites and spines. Under disease conditions, Tau is hyperphosphorylated and accumulates in the somatodendritic domain of neurons including spines. Recent data suggest that dendritic spine-targeted Tau disrupts synaptic function and causes synaptic loss long before neurofibrillary tangle formation and neuronal loss occurs.Fyn is a non-receptor tyrosine kinase that mainly targets to the postsynaptic membrane in spines. Fyn interacts with and phosphorylates Tau and this interaction has a critical role in mediating Aβ toxicity. Understanding how Tau and Fyn are targeted to the dendritic spine and how their trafficking and interaction is regulated under both physiological and pathological conditions is critical for understanding how AD is initiated in the synapse and for developing novel therapeutic approaches to delay, halt or treat AD.Fyn phosphorylates Tau mainly at Tyr18; however, it is unclear how tyrosine phosphorylation of Tau by Fyn affects serine/ threonine phosphorylation. In the first part of my thesis, I have generated a transgenic animal model that expresses constitutively active Fyn and studied the functional consequence of Fyn activation, especially for Tau. We found that FynCA animals showed premature lethality and hyperactive phenotypes reflecting the synaptic over-excitation by Fyn as expected. A biochemical analysis of isolated synaptosomes revealed increased levels of the NMDA receptor subunit NR2b phosphorylated at residue Y1472, and of Tau phosphorylated at the 12E8 phosphoepitope S262/S356. Besides, Tau phosphorylation at the AT8 epitope S202/T205 was strongly increased in FynCA mice as revealed by both immunohistochemistry and Western blot analysis. Our results indicate that an increased tyrosine kinase activity of Fyn has a role in serine/threonine-directed phosphorylation of Tau, which may contribute to the tauopathy in AD. 3 Under physiological conditions, low levels of Tau are targeted to dendritic spines in a process that is regulated by synaptic activity and Aβ levels. It has also been reported that hyperphosphorylated Tau mislocalizes into the spine, although it is not clear what kind of phosphorylation is required. In order to understand how Tau enters the spines and the role of Fyn in dendritic spine targeting of Tau, we performed an extensive mutagenesis study by overexpressing different mutant forms of Tau in cultured wildtype or FynKO neurons.Our results revealed that the spine localization of Tau is facilitated by deletion of the microtubule-binding repeat domain. Distinct pseudophosphorylation at AD related sites AT180(...

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Protein with tau-like repeats regulates neuronal integrity and lifespan inC. elegans

Cited by 52 publications

References 63 publications

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

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

Visualizing the microtubule-associated protein tau in the nucleus

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

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