bims-proarb 2022-08-21 papers

bims-proarb

Biomed News

on Proteostasis in aging and regenerative biology

Issue of 2022–08–21
eleven papers selected by
Rich Giadone, Harvard University

Reduced bone morphogenic protein signaling along the gut-neuron axis by heat shock factor promotes longevity.
Astrocyte-secreted glypican-4 drives APOE4-dependent tau hyperphosphorylation.
Argonaute-dependent ribosome-associated protein quality control.
De novo designed protein inhibitors of amyloid aggregation and seeding.
Chloroplast proteostasis: A story of birth, life and death.
Resilience through selective translation.
Widespread cell stress and mitochondrial dysfunction occur in patients with early Alzheimer's disease.
Palmitate and thapsigargin have contrasting effects on ER membrane lipid composition and ER proteostasis in neuronal cells.
The Role of Amyloid-β, Tau, and α-Synuclein Proteins as Putative Blood Biomarkers in Patients with Cerebral Amyloid Angiopathy.
ER and Golgi trafficking in axons, dendrites, and glial processes.
Spliced X-box binding protein 1 (XBP1s) protects spermatogonial stem cells (SSCs) from lipopolysaccharide (LPS)-induced damage by regulating the testicular microenvironment.

Aging Cell. 2022 Aug 17. e13693

Reduced bone morphogenic protein signaling along the gut-neuron axis by heat shock factor promotes longevity.

Sonja L B Arneaud, Jacob McClendon, Lexus Tatge, Abigail Watterson, Kielen R Zuurbier, Bhoomi Madhu, Tina L Gumienny, Peter M Douglas.

  Aging is a complex and highly regulated process of interwoven signaling mechanisms. As an ancient transcriptional regulator of thermal adaptation and protein homeostasis, the Heat Shock Factor, HSF-1, has evolved functions within the nervous system to control age progression; however, the molecular details and signaling dynamics by which HSF-1 modulates age across tissues remain unclear. Herein, we report a nonautonomous mode of age regulation by HSF-1 in the Caenorhabditis elegans nervous system that works through the bone morphogenic protein, BMP, signaling pathway to modulate membrane trafficking in peripheral tissues. In particular, HSF-1 represses the expression of the neuron-specific BMP ligand, DBL-1, and initiates a complementary negative feedback loop within the intestine. By reducing receipt of DBL-1 in the periphery, the SMAD transcriptional coactivator, SMA-3, represses the expression of critical membrane trafficking regulators including Rab GTPases involved in early (RAB-5), late (RAB-7), and recycling (RAB-11.1) endosomal dynamics and the BMP receptor binding protein, SMA-10. This reduces cell surface residency and steady-state levels of the type I BMP receptor, SMA-6, in the intestine and further dampens signal transmission to the periphery. Thus, the ability of HSF-1 to coordinate BMP signaling along the gut-brain axis is an important determinate in age progression.

Keywords:  BMP signaling; HSF-1; Rab GTPases; SMAD; TGF-β; aging; endocytosis; gut-neuron axis; membrane traffic

DOI:  https://doi.org/10.1111/acel.13693
Proc Natl Acad Sci U S A. 2022 Aug 23. 119(34): e2108870119

Astrocyte-secreted glypican-4 drives APOE4-dependent tau hyperphosphorylation.

Sivaprakasam R Saroja, Kirill Gorbachev, Tcw Julia, Alison M Goate, Ana C Pereira.

  Tau protein aggregates are a major driver of neurodegeneration and behavioral impairments in tauopathies, including in Alzheimer's disease (AD). Apolipoprotein E4 (APOE4), the highest genetic risk factor for late-onset AD, has been shown to exacerbate tau hyperphosphorylation in mouse models. However, the exact mechanisms through which APOE4 induces tau hyperphosphorylation remains unknown. Here, we report that the astrocyte-secreted protein glypican-4 (GPC-4), which we identify as a binding partner of APOE4, drives tau hyperphosphorylation. We discovered that first, GPC-4 preferentially interacts with APOE4 in comparison to APOE2, considered to be a protective allele to AD, and second, that postmortem APOE4-carrying AD brains highly express GPC-4 in neurotoxic astrocytes. Furthermore, the astrocyte-secreted GPC-4 induced both tau accumulation and propagation in vitro. CRISPR/dCas9-mediated activation of GPC-4 in a tauopathy mouse model robustly induced tau hyperphosphorylation. In the absence of GPC4, APOE4-induced tau hyperphosphorylation was largely diminished using in vitro tau fluorescence resonance energy transfer-biosensor cells, in human-induced pluripotent stem cell-derived astrocytes and in an in vivo mouse model. We further show that APOE4-mediated surface trafficking of APOE receptor low-density lipoprotein receptor-related protein 1 through GPC-4 can be a gateway to tau spreading. Collectively, these data support that APOE4-induced tau hyperphosphorylation is directly mediated by GPC-4.

Keywords:  APOE4; Alzheimer’s disease; astrocytes; glypican-4; tau pathology

DOI:  https://doi.org/10.1073/pnas.2108870119
Trends Cell Biol. 2022 Aug 16. pii: S0962-8924(22)00188-X. [Epub ahead of print]

Argonaute-dependent ribosome-associated protein quality control.

Yajie Gao, Yuanxiang Zhu, Qinmiao Sun, Dahua Chen.

  Ribosome-associated protein quality control (RQC) is a protein surveillance mechanism that eliminates defective nascent polypeptides. The E3 ubiquitin ligase, Ltn1, is a key regulator of RQC that targets substrates for ubiquitination. Argonaute proteins (AGOs) are central players in miRNA-mediated gene silencing and have recently been shown to also regulate RQC by facilitating Ltn1. Therefore, AGOs directly coordinate post-transcriptional gene silencing and RQC, ensuring efficient gene silencing. We summarize the principles of RQC and the functions of AGOs in miRNA-mediated gene silencing, and discuss how AGOs associate with the endoplasmic reticulum (ER) to assist Ltn1 in controlling RQC. We highlight that RQC not only eliminates defective nascent polypeptides but also removes unwanted protein products when AGOs participate.

Keywords:  Ltn1; RNA-induced gene silencing; VCP; ribosome stalling; ubiquitin

DOI:  https://doi.org/10.1016/j.tcb.2022.07.007
Proc Natl Acad Sci U S A. 2022 Aug 23. 119(34): e2206240119

De novo designed protein inhibitors of amyloid aggregation and seeding.

Kevin A Murray, Carolyn J Hu, Sarah L Griner, Hope Pan, Jeannette T Bowler, Romany Abskharon, Gregory M Rosenberg, Xinyi Cheng, Paul M Seidler, David S Eisenberg.

  Neurodegenerative diseases are characterized by the pathologic accumulation of aggregated proteins. Known as amyloid, these fibrillar aggregates include proteins such as tau and amyloid-β (Aβ) in Alzheimer's disease (AD) and alpha-synuclein (αSyn) in Parkinson's disease (PD). The development and spread of amyloid fibrils within the brain correlates with disease onset and progression, and inhibiting amyloid formation is a possible route toward therapeutic development. Recent advances have enabled the determination of amyloid fibril structures to atomic-level resolution, improving the possibility of structure-based inhibitor design. In this work, we use these amyloid structures to design inhibitors that bind to the ends of fibrils, "capping" them so as to prevent further growth. Using de novo protein design, we develop a library of miniprotein inhibitors of 35 to 48 residues that target the amyloid structures of tau, Aβ, and αSyn. Biophysical characterization of top in silico designed inhibitors shows they form stable folds, have no sequence similarity to naturally occurring proteins, and specifically prevent the aggregation of their targeted amyloid-prone proteins in vitro. The inhibitors also prevent the seeded aggregation and toxicity of fibrils in cells. In vivo evaluation reveals their ability to reduce aggregation and rescue motor deficits in Caenorhabditis elegans models of PD and AD.

Keywords:  alpha-synuclein; amyloid; amyloid-beta; protein design; tau

DOI:  https://doi.org/10.1073/pnas.2206240119
Plant Commun. 2022 Aug 12. pii: S2590-3462(22)00256-5. [Epub ahead of print] 100424

Chloroplast proteostasis: A story of birth, life and death.

Lin-Lin Gao, Zheng-Hui Hong, Yinsong Wang, Guo-Zhang Wu.

  Protein homeostasis (proteostasis) is a dynamic balance of protein synthesis and degradation. Because of the endosymbiotic origin of the chloroplasts and the massive transfer of their genetic information to the nucleus of the host cell, many protein complexes in the chloroplasts are constituted by subunits encoded by both genomes. Hence, the proper function of chloroplasts relies on the coordinated expression of chloroplast- and nucleus-encoded genes. The biogenesis and maintenance of chloroplast proteostasis are dependent on the synthesis of chloroplast-encoded proteins, import of nucleus-encoded chloroplast proteins from the cytosol, and clearance of damaged or otherwise undesired "old" proteins. This review focuses on the regulation of chloroplast proteostasis, the interaction with the proteostasis of the cytosol and its retrograde control to the nuclear gene expression. We also discuss the significant issues and perspectives for the future studies, and the potential applications to improve the photosynthetic performance and stress tolerance of crops.

Keywords:  chloroplast; interaction; proteostasis; retrograde signaling; stress

DOI:  https://doi.org/10.1016/j.xplc.2022.100424
Nat Rev Mol Cell Biol. 2022 Aug 18.

Resilience through selective translation.

Julia Bailey-Serres.

DOI: https://doi.org/10.1038/s41580-022-00532-4
Sci Transl Med. 2022 Aug 17. 14(658): eabk1051

Widespread cell stress and mitochondrial dysfunction occur in patients with early Alzheimer's disease.

Ashwin V Venkataraman, Ayla Mansur, Gaia Rizzo, Courtney Bishop, Yvonne Lewis, Ece Kocagoncu, Anne Lingford-Hughes, Mickael Huiban, Jan Passchier, James B Rowe, Hideo Tsukada, David J Brooks, Laurent Martarello, Robert A Comley, Laigao Chen, Adam J Schwarz, Richard Hargreaves, Roger N Gunn, Eugenii A Rabiner, Paul M Matthews.

Cell stress and impaired oxidative phosphorylation are central to mechanisms of synaptic loss and neurodegeneration in the cellular pathology of Alzheimer's disease (AD). In this study, we quantified the in vivo expression of the endoplasmic reticulum stress marker, sigma 1 receptor (S1R), using [11C]SA4503 positron emission tomography (PET), the mitochondrial complex I (MC1) with [18F]BCPP-EF, and the presynaptic vesicular protein SV2A with [11C]UCB-J in 12 patients with early AD and in 16 cognitively normal controls. We integrated these molecular measures with assessments of regional brain volumes and cerebral blood flow (CBF) measured with magnetic resonance imaging arterial spin labeling. Eight patients with AD were followed longitudinally to estimate the rate of change of the physiological and structural pathology markers with disease progression. The patients showed widespread increases in S1R (≤ 27%) and regional reduction in MC1 (≥ -28%) and SV2A (≥ -25%) radioligand binding, brain volume (≥ -23%), and CBF (≥ -26%). [18F]BCPP-EF PET MC1 binding (≥ -12%) and brain volumes (≥ -5%) showed progressive reductions over 12 to 18 months, suggesting that they both could be used as pharmacodynamic indicators in early-stage therapeutics trials. Associations of reduced MC1 and SV2A and increased S1R radioligand binding with reduced cognitive performance in AD, although exploratory, suggested a loss of metabolic functional reserve with disease. Our study thus provides in vivo evidence for widespread, clinically relevant cellular stress and bioenergetic abnormalities in early AD.

DOI: https://doi.org/10.1126/scitranslmed.abk1051
Biochim Biophys Acta Mol Cell Biol Lipids. 2022 Aug 15. pii: S1388-1981(22)00109-3. [Epub ahead of print] 159219

Palmitate and thapsigargin have contrasting effects on ER membrane lipid composition and ER proteostasis in neuronal cells.

Maria H Jäntti, Shelley Jackson, Jeffrey Kuhn, Ilmari Parkkinen, Sreesha Sree, Joshua Hinkle, Eija Jokitalo, Leesa Deterding, Brandon K Harvey.

  The endoplasmic reticulum (ER) is an organelle that performs several key functions such as protein synthesis and folding, lipid metabolism and calcium homeostasis. When these functions are disrupted, such as upon protein misfolding, ER stress occurs. ER stress can trigger adaptive responses to restore proper functioning such as activation of the unfolded protein response (UPR). In certain cells, the free fatty acid palmitate has been shown to induce the UPR. Here, we examined the effects of palmitate on UPR gene expression in a human neuronal cell line and compared it with thapsigargin, a known depletor of ER calcium and trigger of the UPR. We used a Gaussia luciferase-based reporter to assess how palmitate treatment affects ER proteostasis and calcium homeostasis in the cells. We also investigated how ER calcium depletion by thapsigargin affects lipid membrane composition by performing mass spectrometry on subcellular fractions and compared this to palmitate. Surprisingly, palmitate treatment did not activate UPR despite prominent changes to membrane phospholipids. Conversely, thapsigargin induced a strong UPR, but did not significantly change the membrane lipid composition in subcellular fractions. In summary, our data demonstrate that changes in membrane lipid composition and disturbances in ER calcium homeostasis have a minimal influence on each other in neuronal cells. These data provide new insight into the adaptive interplay of lipid homeostasis and proteostasis in the cell.

Keywords:  Brain lipids; Cell signaling; ER calcium; Endoplasmic reticulum; Exodosis; Lipidomics; Lipids; Palmitate; Phospholipids; Thapsigargin; UPR; Unfolded protein response

DOI:  https://doi.org/10.1016/j.bbalip.2022.159219
J Alzheimers Dis. 2022 Aug 09.

The Role of Amyloid-β, Tau, and α-Synuclein Proteins as Putative Blood Biomarkers in Patients with Cerebral Amyloid Angiopathy.

Rebecca Piccarducci, Maria Chiara Caselli, Elisa Zappelli, Leonardo Ulivi, Simona Daniele, Gabriele Siciliano, Roberto Ceravolo, Michelangelo Mancuso, Filippo Baldacci, Claudia Martini.

   BACKGROUND: Cerebral amyloid angiopathy (CAA) is a cerebrovascular disorder characterized by the deposition of amyloid-β protein (Aβ) within brain blood vessels that develops in elderly people and Alzheimer's disease (AD) patients. Therefore, the investigation of biomarkers able to differentiate CAA patients from AD patients and healthy controls (HC) is of great interest, in particular in peripheral fluids.
OBJECTIVE: The current study aimed to detect the neurodegenerative disease (ND)-related protein (i.e., Aβ 1 - 40, Aβ 1 - 42, tau, and α-synuclein) levels in both red blood cells (RBCs) and plasma of CAA patients and HC, evaluating their role as putative peripheral biomarkers for CAA.
METHODS: For this purpose, the proteins' concentration was quantified in RBCs and plasma by homemade immunoenzymatic assays in an exploratory cohort of 20 CAA patients and 20 HC.
RESULTS: The results highlighted a significant increase of Aβ 1 - 40 and α-synuclein concentrations in both RBCs and plasma of CAA patients, while higher Aβ 1 - 42 and t-tau levels were detected only in RBCs of CAA individuals compared to HC. Moreover, Aβ 1 - 42/Aβ 1 - 40 ratio increased in RBCs and decreased in plasma of CAA patients. The role of these proteins as candidate peripheral biomarkers easily measurable with a blood sample in CAA needs to be confirmed in larger studies.
CONCLUSION: In conclusion, we provide evidence concerning the possible use of blood biomarkers for contributing to CAA diagnosis and differentiation from other NDs.

Keywords:  amyloid-β; biomarkers; cerebral amyloid angiopathy; plasma; red blood cells; tau; α-synuclein

DOI:  https://doi.org/10.3233/JAD-220216
Curr Opin Cell Biol. 2022 Aug 11. pii: S0955-0674(22)00072-2. [Epub ahead of print]78 102119

ER and Golgi trafficking in axons, dendrites, and glial processes.

Shahrnaz Kemal, Hunter S Richardson, Eric D Dyne, Meng-Meng Fu.

Both neurons and glia in mammalian brains are highly ramified. Neurons form complex neural networks using axons and dendrites. Axons are long with few branches and form pre-synaptic boutons that connect to target neurons and effector tissues. Dendrites are shorter, highly branched, and form post-synaptic boutons. Astrocyte processes contact synapses and blood vessels in order to regulate neuronal activity and blood flow, respectively. Oligodendrocyte processes extend toward axons to make myelin sheaths. Microglia processes dynamically survey their environments. Here, we describe the local secretory system (ER and Golgi) in neuronal and glial processes. We focus on Golgi outpost functions in acentrosomal microtubule nucleation, cargo trafficking, and protein glycosylation. Thus, satellite ER and Golgi are critical for local structure and function in neurons and glia.

DOI: https://doi.org/10.1016/j.ceb.2022.102119
Theriogenology. 2022 Aug 03. pii: S0093-691X(22)00279-5. [Epub ahead of print]191 132-140

Spliced X-box binding protein 1 (XBP1s) protects spermatogonial stem cells (SSCs) from lipopolysaccharide (LPS)-induced damage by regulating the testicular microenvironment.

Wenjing Xu, Yumei Yang, Yunxiang Li, Donghui Yang, Shicheng Wan, Na Li, Jinlian Hua.

  XBP1 is a transcription factor that plays a central role in controlling cellular responses to endoplasmic reticulum stress (ERS). Under stress conditions, the transcriptionally active form of XBP1 is generated by splicing of XBP1 mRNA by the ER-resident protein inositol-requiring enzyme-1α (IRE1α). This study aimed to investigate the role of XBP1 in male reproductive disorders. XBP1s-overexpressing goat spermatogonial stem cells (gSSCs) showed higher proliferative ability in vitro and in vivo. These cells also showed higher antioxidant capacity. In comparison, XBP1 knockdown significantly suppressed proliferation. Further analysis showed that XBP1 could stimulate the secretion of IL-6 from macrophages. Overall, the results indicate that XBP1s functions to enhance the proliferation ability and antioxidant capacity of gSSCs, potentially through a mechanism involving the regulation of gSSCs by macrophages.

Keywords:  Goat; Proliferation; SSCs; XBP1s

DOI:  https://doi.org/10.1016/j.theriogenology.2022.07.014