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Abstract Microtubule‐associated protein tau is an intrinsically disordered, highly soluble protein found primarily in neurons. Under normal conditions, tau regulates the stability of axonal microtubules and intracellular vesicle transport. However, in patients of neurodegeneration such as Alzheimer's disease (AD), tau forms neurofibrillary deposits, which correlates well with the disease progression. Identifying molecular signatures in tau, such as posttranslational modification, truncation, and conformational change has great potential to detect earliest signs of neurodegeneration and develop therapeutic strategies. Here, we show that full‐length human tau, including the longest isoform found in the adult brain, can be robustly displayed on the surface of yeastSaccharomyces cerevisiae. Yeast‐displayed tau binds to anti‐tau antibodies that cover epitopes ranging from the N‐terminus to the 4R repeat region. Unlike tau expressed in the yeast cytosol, surface‐displayed tau was not phosphorylated at sites found in AD patients (probed by antibodies AT8, AT270, AT180, and PHF‐1). However, yeast‐displayed tau showed clear binding to paired helical filament (PHF) tau conformation‐specific antibodies Alz‐50, MC‐1, and Tau‐2. Although the tau possessed a conformation found in PHFs, oligomerization or aggregation into larger filaments was undetected. Taken together, yeast‐displayed tau enables robust measurement of protein interactions and is of particular interest for characterizing conformational change.
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Regulation of proteostasis by sleep through autophagy in Drosophila models of Alzheimer’s disease
Sleep and circadian rhythm dysfunctions are common clinical features of Alzheimer’s disease (AD). Increasing evidence suggests that in addition to being a symptom, sleep disturbances can also drive the progression of neurodegeneration. Protein aggregation is a pathological hallmark of AD; however, the molecular pathways behind how sleep affects protein homeostasis remain elusive. Here we demonstrate that sleep modulation influences proteostasis and the progression of neurodegeneration inDrosophilamodels of tauopathy. We show that sleep deprivation enhanced Tau aggregational toxicity resulting in exacerbated synaptic degeneration. In contrast, sleep induction using gaboxadol led to reduced toxic Tau accumulation in neurons as a result of modulated autophagic flux and enhanced clearance of ubiquitinated Tau, suggesting altered protein processing and clearance that resulted in improved synaptic integrity and function. These findings highlight the complex relationship between sleep and regulation of protein homeostasis and the neuroprotective potential of sleep-enhancing therapeutics to slow the progression or delay the onset of neurodegeneration.
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- Award ID(s):
- 2131037
- PAR ID:
- 10592638
- Publisher / Repository:
- Life Science Alliance
- Date Published:
- Journal Name:
- Life Science Alliance
- Volume:
- 7
- Issue:
- 11
- ISSN:
- 2575-1077
- Page Range / eLocation ID:
- e202402681
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.26508/lsa.202402681
