bims-naurep 2025-12-21 papers

bims-naurep

Biomed News

on Non-autonomous regulation of proteostasis

Issue of 2025–12–21
nineteen papers selected by
Franziska Hommen-puhl, Uniklinik Köln

The microRNA miR-71 suppresses maladaptive UPRmt signaling through both cell-autonomous and cell-non-autonomous mechanisms.
Stress-specific NONO interactomes reveal a key role of Hsp70 chaperone activity in regulation of paraspeckle formation.
Krüppel-like factor 1 acts upstream of the SKN-1/Nrf transcription factors to modulate oxidative stress, lipid homeostasis and longevity.
Subcellular In Vivo Cardiac Proteomics Reveals Sarcomere and Ribosome Interactomes and skNAC's Impact on Cardiac Proteostasis.
Mistranslating tRNA variants impact the proteome and phosphoproteome of Saccharomyces cerevisiae.
Deep Profiling of the Aging Proteome Depicts Neuroinflammation, Synaptic Function, and Phosphorylation in an Accelerated Alzheimer's Disease Cell Model.
The pos-1 3' untranslated region governs germline specification and proliferation to ensure reproductive robustness.
Regulation of vacuole fusion in stomata by dephosphorylation of the HOPS subunit VPS39.
The G3BP stress-granule proteins reinforce the integrated stress response translation programme.
Vesicular Rps6 Released by Astrocytes in an Experimental Model of AD Regulates Local Translation and Enhances Synaptic Integrity in Neurones.
Structural variability of multifunctional proteins indicates frequent stochastic evolution of protein oligomers.
The ubiquitin-proteasome system in Alzheimer's disease: mechanism of action and current status of treatment.
Protein aggregates and biomolecular condensates: implications for human health and disease.
Neuronal APOE4 alone is sufficient to drive tau pathology, neurodegeneration, and neuroinflammation in an Alzheimer's disease mouse model.
The role and interplay among Autophagy, Apoptosis, and ferroptosis in acute pancreatitis: mechanisms and therapeutic approaches.
Differential Regulation of APOE4-Mediated Astrocytic Lipid Metabolism by BMP Signaling Exacerbates Alzheimer's Disease Pathologies in Neurons.
Diapause and Aging: Two opposing yet intertwined biological phenomena.
Age-dependent topoisomerase I depletion alters recruitment of rDNA silencing complexes.
Novel Roles for the Ectoenzyme CD38 in the Maintenance of Transcriptional and Metabolic Homeostasis in Astrocytes.

Nat Commun. 2025 Dec 14.

The microRNA miR-71 suppresses maladaptive UPRmt signaling through both cell-autonomous and cell-non-autonomous mechanisms.

Ina Kirmes, Grace Ching Ching Hung, Anne Hahn, Chuan-Yang Dai, Daniel Campbell, Arnaud Ahier, Rachel Shin Yie Lee, Alexander Palmer, Steven Zuryn.

Mitochondria play a central role in metabolism and biosynthesis, but function also as platforms that perceive and communicate environmental and physiological stressors to the nucleus and distal tissues. Systemic mitochondrial signaling is thought to synchronize and amplify stress responses throughout the whole body, but during severe or chronic damage, overactivation of mitochondrial stress pathways may be maladaptive and exacerbate aging and metabolic disorders. Here we uncover a protective micro(mi)RNA response to mtDNA damage in Caenorhabditis elegans that prolongs tissue health and function by interfering with mitochondrial stress signaling. Acting within muscle cells, we show that the miRNA miR-71 is induced during severe mitochondrial damage by the combined activities of DAF-16, HIF-1, and ATFS-1, where it restores sarcomere structure and animal locomotion by directly suppressing the inordinate activation of DVE-1, a key regulator of the mitochondrial unfolded protein response (UPRmt). Indirectly, miR-71 also reduces the levels of multiple neuro- and insulin-like peptides and their secretion machinery, resulting in decreased cell-non-autonomous signaling of mitochondrial stress from muscle to glia cells. miR-71 therefore beneficially coordinates the suppression of both local and systemic mitochondrial stress pathways during severe organelle dysfunction. These findings open the possibility that metabolic disorders could be ameliorated by limiting the overactivation of mitochondrial stress responses through targeted small RNAs.

DOI: https://doi.org/10.1038/s41467-025-67198-2
J Cell Sci. 2025 Dec 19. pii: jcs.264115. [Epub ahead of print]

Stress-specific NONO interactomes reveal a key role of Hsp70 chaperone activity in regulation of paraspeckle formation.

Isaac Odonkor, Birendra Kumar Shrestha, Stephanie Rose Nielsen, Athanasios Kournoutis, Ida Emilie Bjørlo, Saikat Das Sajib, Annica Hedberg, Toril Anne Grønset, Kenneth Bowitz Larsen, Jack-Ansgar Brun, Erik Knutsen, Seyed Mohammad Lellahi, Maria Perander.

  Paraspeckles are stress-induced nuclear RNA-protein condensates that assemble on the long non-coding RNA NEAT1. Their increased formation under certain cellular circumstances has gained growing interest due to their association with serious human diseases such as neurodegenerative disorders and cancer. The biological functions of paraspeckles still appear obscure, but increasing evidence suggests that they contribute to regulation of gene expression by recruiting specific proteins and RNA molecules. Here, we have characterized and compared two stress-enriched interactomes of the essential paraspeckle protein NONO in both wild type and paraspeckle-deficient NEAT1 knockout cells. We identified Hsp70 as part of stress-enriched NONO complexes in wild type, but not in NEAT1-depleted cells. We show that proteotoxic stress-induced paraspeckle formation and NEAT1 expression are strictly dependent on Hsp70 chaperone activity. Our data demonstrate that both NONO and Hsp70 transiently translocate to the nucleolus during heat shock and that paraspeckle formation during recovery follows Hsp70-dependent relocation of NONO from the nucleolus to the nucleoplasm. Taken together, we demonstrate an important role of Hsp70 in paraspeckle assembly and identify a possible link between the nuclear protein quality control system and paraspeckles.

Keywords:   NEAT1 ; Cellular stress responses; Heat shock response; Hsp70; NONO; Paraspeckles; Proteostasis; TurboID

DOI:  https://doi.org/10.1242/jcs.264115
bioRxiv. 2025 Nov 25. pii: 2025.11.22.689963. [Epub ahead of print]

Krüppel-like factor 1 acts upstream of the SKN-1/Nrf transcription factors to modulate oxidative stress, lipid homeostasis and longevity.

Jorge Iván Castillo-Quan, Aiden McCarty, Ugne Kurdeikaite, Katherine Gilmore, Arlette Cabral, Justin Mejia, Julia Barrett, Maria La Terza, Emma Johnson, Allison Carroll, T Keith Blackwell, Jean E Schaffer, Natalie Moroz.

Maintenance of lipid and redox homeostasis are essential for stress resistance and longevity, but the transcriptional networks coordinating these processes remain incompletely understood. In Caenorhabditis elegans , the transcription factors SKN-1A/Nrf1 and SKN-1C/Nrf2 mediate distinct stress responses that promote proteostasis, lipid homeostasis, and oxidative stress. Here we identify the Krüppel-like factor KLF-1 as a critical upstream regulator of both SKN-1A and SKN-1C. We show that KLF-1 is required for the oxidative stress resistance and longevity of germline-deficient animals. Genetic interaction studies showed that KLF-1 acts in parallel to the lipogenic regulator Sterol regulatory element-Binding Protein 1 (SBP-1/SREBP1), whereas the related KLF-2 exerts opposing effects on lipid accumulation through SBP-1. Together, these findings place KLF-1 and KLF-2 within a transcriptional network that integrates lipid metabolism, oxidative stress responses, and aging. This work uncovers a conserved regulatory network linking KLFs and SKN-1/Nrf transcription factors in the maintenance of lipid homeostasis and longevity assurance.

DOI: https://doi.org/10.1101/2025.11.22.689963
Circ Res. 2025 Dec 15.

Subcellular In Vivo Cardiac Proteomics Reveals Sarcomere and Ribosome Interactomes and skNAC's Impact on Cardiac Proteostasis.

Rami Haddad, Omer Sadeh, Tamar Ziv, Nardeen Shehdeh, Nadav Keren, Izhak Kehat.

   BACKGROUND: Proteostasis and the regulation of protein folding and sorting play a critical role in maintaining cellular homeostasis. The failure of proteostasis contributes to heart failure and aging, but, despite its importance, the mechanisms and factors regulating proteostasis in cardiomyocytes remain poorly characterized.
METHODS: Subcellular proteomes of cardiomyocytes were analyzed in vivo using biotin proximity labeling in mouse hearts. We employed a novel homology-independent targeting integration strategy for genetic tagging and for substitution of the muscle-specific skNAC (skeletal nascent polypeptide-associated complex alpha isoform) isoform with the ubiquitous short isoform in cardiomyocytes.
RESULTS: We identified hundreds of proteins localized to the Z- and M-lines of sarcomeres, the ribosomes, and the desmosomes, including multiple chaperones. A universal homology-independent targeted integration strategy allowed us to genetically tag endogenous genes in the mouse heart and confirm protein localization. We identified the large muscle-specific isoform of the nascent polypeptide-associated complex protein skNAC as a Z-line and ribosome-associated protein. Replacement of skNAC with a ubiquitous isoform induced dilated cardiomyopathy, accompanied by altered ribosome positioning and markedly reduced mitochondrial protein levels.
CONCLUSIONS: We unraveled the cardiomyocyte subcellular proteome and show that skNAC, an isoform downregulated in disease, is a key ribosome and Z-line-associated protein responsible for cardiomyocyte proteostasis.

Keywords:  biotin; desmosomes; heart failure; mitochondria; proteostasis

DOI:  https://doi.org/10.1161/CIRCRESAHA.125.326929
G3 (Bethesda). 2025 Dec 17. pii: jkaf284. [Epub ahead of print]

Mistranslating tRNA variants impact the proteome and phosphoproteome of Saccharomyces cerevisiae.

Matthew D Berg, Alexis T Chang, Ricard A Rodriguez-Mias, Judit Villén.

  Transfer RNAs (tRNAs) ensure accurate decoding of the genetic code. However, mutations in tRNAs can lead to misincorporation of an amino acid that differs from the genetic message in a process known as mistranslation. As mistranslating tRNAs modify how the genetic message is decoded, they have potential as therapeutic tools for diseases caused by nonsense and missense mutations. Despite this, they also produce proteome-wide mismade proteins, which can disrupt proteostasis. To better understand the impact of mistranslating tRNA variants, we profile the proteome and phosphoproteome of yeast expressing three different mistranslating tRNAs. While the overall impacts were similar, the extent of growth defects and proteome changes varied with the substitution type. Although the global impacts were modest, mistranslation influenced key cellular processes, including proteostasis, cell cycle, and translation. These findings highlight the need to consider cellular consequences when developing mistranslating tRNAs for therapeutic applications.

Keywords:  mass spectrometry; mistranslation; phosphoproteomics; proteomics; proteostasis; tRNA biology

DOI:  https://doi.org/10.1093/g3journal/jkaf284
Mol Cell Proteomics. 2025 Dec 17. pii: S1535-9476(25)00589-4. [Epub ahead of print] 101490

Deep Profiling of the Aging Proteome Depicts Neuroinflammation, Synaptic Function, and Phosphorylation in an Accelerated Alzheimer's Disease Cell Model.

Emma Gentry, Md Tarikul Islam, Huijing Xue, Kan Cao, Peter Nemes.

  Alzheimer's disease (AD) is an age-associated neurodegenerative disorder characterized by amyloid plaques, tau hyperphosphorylation, and synaptic dysfunction. Most available cellular AD models lack aging features, limiting their ability to recapitulate key pathological mechanisms. Here we applied high-resolution mass spectrometry-based multiplexed proteomics and phosphoproteomics in a discovery setting to characterize an accelerated AD (acAD) model that combines amyloid precursor protein (APP) and presenilin (PSEN) mutations with progerin, an aging-associated Lamin A mutant that accelerates aging. Across four phenotypes (control, progerin, classic AD, and acAD), we quantified 6,081 proteins and detected phosphorylation dynamics. Relative to the classic model, acAD exhibited broader proteome remodeling, including amplified downregulation of synaptic and cytoskeletal proteins, upregulation of transcription and translation machinery, and pathway-level changes in neuronal signaling, mitochondrial dynamics, and neuroinflammation. Phosphoproteome analysis revealed widespread changes in RNA-binding and cytoskeletal proteins, aligning with recent data from two murine AD models. These findings show that acAD captures canonical AD phenotypes while uniquely modeling age-related inflammation and phosphorylation, providing a resource to accelerate studies of proteome-level mechanisms of AD progression and to inform strategies targeting cytoskeletal and inflammatory pathways.

Keywords:  Aging; Alzheimer’s disease; biomarkers; mass spectrometry; neuroinflammation; profiling; proteomics

DOI:  https://doi.org/10.1016/j.mcpro.2025.101490
bioRxiv. 2025 Nov 28. pii: 2025.11.26.690476. [Epub ahead of print]

The pos-1 3' untranslated region governs germline specification and proliferation to ensure reproductive robustness.

Haik V Varderesian, Juliet N Utaegbulam, Hannah E Brown, Beverly Ramirez, Melina Velcani, Sean P Ryder.

During fertilization, haploid gametes combine to form a zygote. The male (sperm) and female (oocyte) gametes contribute a similar amount of DNA, but the oocyte contributes nearly all the cytoplasm. Oocytes are loaded with maternal mRNAs thought to be essential for embryonic patterning after fertilization. A conserved suite of RNA-binding proteins (RBPs) regulates the spatiotemporal translation and stability of maternal mRNAs. POS-1 is a CCCH-type tandem zinc finger RBP expressed in fertilized Caenorhabditis elegans zygotes from maternally supplied mRNA. POS-1 accumulates in the posterior of the embryo where it promotes posterior cell fate. Here, we show that the pos-1 3' untranslated region (UTR) is essential for POS-1 patterning and contributes to maximal reproductive fecundity. We engineered a pos-1 mutant where most of the endogenous pos-1 3'UTR was removed using CRISPR genome editing. Our results show that the 3'UTR represses POS-1 expression in the maternal germline but increases POS-1 protein levels in embryos after fertilization. In a wild-type background, POS-1 repression via the 3'UTR has little impact on fertility. In a sensitized background, the deletion mutant has a complex pleiotropic phenotype where most adult homozygous progeny lack either one or both gonad arms. Most phenotypes become more penetrant at elevated temperature. Together, our results support an emerging model where the 3'UTRs of maternal transcripts, rather than being essential, contribute to reproductive robustness during stress.

DOI: https://doi.org/10.1101/2025.11.26.690476
Plant J. 2025 Dec;124(6): e70640

Regulation of vacuole fusion in stomata by dephosphorylation of the HOPS subunit VPS39.

Anne-Marie Pullen, Grant Billings, Charles Hodgens, Gisele White, Belinda S Akpa, Marcela Rojas-Pierce.

  Understanding how plants regulate water loss is important for improving crop productivity. Tight control of stomatal opening and closing is essential for the uptake of CO2 while mitigating water vapor loss. The opening of stomata is regulated in part by homotypic vacuole fusion, which is mediated by conserved homotypic vacuole protein sorting (HOPS) and vacuolar SNARE (soluble N-ethylmaleimide sensitive factor attachment protein receptors) complexes. HOPS tethers apposing vacuole membranes and promotes the formation of trans-SNARE complexes to mediate fusion. In yeast, HOPS dissociates from the assembled SNARE complex to complete vacuole fusion, but little is known about this process in plants. HOPS-specific subunits VACUOLE PROTEIN SORTING39 (VPS39) and VPS41 are required for homotypic plant vacuole fusion, and a computational model predicted that post-translational modifications of HOPS may be needed for plant stomatal vacuole fusion. Here, we characterized a viable T-DNA insertion allele of VPS39 which demonstrated a critical role of VPS39 in stomatal vacuole fusion. We found that VPS39 has increased levels of phosphorylation at S413 when stomata are closed versus open, and that VPS39 function in stomata and embryonic development requires dynamic changes in phosphorylation. Among all HOPS and vacuolar SNARE subunits, only VPS39 showed differential levels of phosphorylation between open and closed stomata. Moreover, regions containing S413 are not conserved between plants and other organisms, suggesting plant-specific mechanisms. Our data are consistent with VPS39 phosphorylation altering vacuole dynamics in response to environmental cues, similar to well-established phosphorylation cascades that regulate ion transport during stomatal opening.

Keywords:  HOPS; SNARE; guard cell; membrane fusion; phosphorylation; stomata; vacuole

DOI:  https://doi.org/10.1111/tpj.70640
Nat Cell Biol. 2025 Dec 19.

The G3BP stress-granule proteins reinforce the integrated stress response translation programme.

Jarrett Smith, David P Bartel.

When mammalian cells are exposed to stress, they co-ordinate the condensation of stress granules (SGs) through the action of proteins G3BP1 and G3BP2 (G3BPs) and, simultaneously, undergo a massive reduction in translation. Although SGs and G3BPs have been linked to this translation response, their overall impact has been unclear. Here we investigate the question of how, and indeed whether, G3BPs and SGs shape the stress translation response. We find that SGs are enriched for mRNAs that are resistant to the stress-induced translation shutdown. Although the accurate recruitment of these stress-resistant mRNAs does require the context of stress, a combination of optogenetic tools and spike-normalized ribosome profiling demonstrates that G3BPs and SGs are necessary and sufficient to both help prioritize the translation of their enriched mRNAs and help suppress cytosolic translation. Together, these results support a model in which G3BPs and SGs reinforce the stress translation programme by prioritizing the translation of their resident mRNAs.

DOI: https://doi.org/10.1038/s41556-025-01834-3
J Extracell Vesicles. 2025 Dec;14(12): e70216

Vesicular Rps6 Released by Astrocytes in an Experimental Model of AD Regulates Local Translation and Enhances Synaptic Integrity in Neurones.

María Gamarra, Aida de la Cruz-Gambra, Maite Blanco-Urrejola, Esperanza González, Mikel Azkargorta, Felix Elortza, Juan Manuel Falcón-Pérez, Jimena Baleriola.

  In neurones, like in any other cell, their function often relies on the fine-tuning of their protein levels, which is achieved by the balance between protein synthesis and turnover. Defects in protein homeostasis frequently lead to neuronal dysfunction and neurological disorders. Given their extreme morphological complexity and high compartmentalization, neurones highly depend on the asymmetrical distribution of their proteome. The common belief is that proteins that sustain axonal, dendritic and synaptic functions are synthesized in the soma and then transported to distal neuronal compartments. However, there is a complementary mechanism by which the mRNAs, and not the proteins, are transported to distal subneuronal domains, and once they reach their destination, they are locally translated. Although once considered heretical, local translation (or local protein synthesis) is now widely accepted by the scientific community. Nonetheless, there is one question that remains largely unexplored in the field, and that is whether local translation in dendrites, axons and synapses is fully regulated by the neurone itself or if non-neuronal cells (e.g., glia) can modulate this mechanism in a non-cell-autonomous manner. Here, we combined primary neuronal cultures, astrocyte-derived extracellular vesicle (EVs) isolation, and proteomics to investigate whether astroglial EVs modulate local translation in axons. We show that EVs released by astrocytes exposed to amyloid-β peptide (Aβ) enhance protein synthesis specifically in distal axons and increase synaptic integrity. Proteomics analysis and western blotting identified the ribosomal protein Rps6 as an astroglial Aβ-EV cargo delivered to axons. Interestingly, genetic downregulation revealed the contribution of vesicular Rps6 to translation regulation in axons and synaptic integrity. To our knowledge, this is the first report that directly demonstrates glial control of local translation in neurones through EVs, revealing a novel glia-to-neurone communication mechanism in an experimental model of Alzheimer's disease (AD).

Keywords:  amyloid pathology; astroglia‐derived EVs; intra‐axonal protein synthesis; ribosomal proteins; synapses

DOI:  https://doi.org/10.1002/jev2.70216
Commun Biol. 2025 Dec 13.

Structural variability of multifunctional proteins indicates frequent stochastic evolution of protein oligomers.

György Abrusán, Aleksej Zelezniak.

Recently, it has been suggested that the evolution of many protein homomer complexes follows a neutral pattern, with little effect on their biochemical function. One of the strongest arguments in support of this hypothesis is the observation that homologous enzymes with the same catalytic function can have different quaternary structures in various species. However, in the case of proteins with multiple functions ("moonlighting" proteins), this pattern can also have an adaptive explanation if quaternary structure is responsible for their variable, non-canonical functions. To test whether moonlighting can be responsible for the variability of quaternary structure, here we examine the opposite of the "same function-multiple structures" pattern, and test whether orthogroups of moonlighting (multifunctional) and non-moonlighting proteins have similar quaternary structure variability. We show that there is very little association between moonlighting and homomer quaternary structure diversity, which is in agreement with the neutral expectation and the hypothesis that many homomers might be adaptive by shaping the biophysical characteristics of the cell and cytoplasm, rather than the biochemical function of the protein.

DOI: https://doi.org/10.1038/s42003-025-09183-5
Front Aging Neurosci. 2025 ;17 1730206

The ubiquitin-proteasome system in Alzheimer's disease: mechanism of action and current status of treatment.

Shanshan Jia, Quan Li, Xue Rui, Wen Qin, Wenhui Zhang, Jinjin Dou, Xiwu Zhang.

  Alzheimer's disease (AD) is one of the most common neurodegenerative disorders; current therapies can neither cure AD nor prevent its progression. The pathological hallmark of AD is the excessive deposition of abnormal proteins in the brain, primarily including β-amyloid (Aβ) and phosphorylated Tau proteins. The ubiquitin-proteasome system (UPS), a central intracellular protein degradation mechanism that removes misfolded proteins and maintains cellular homeostasis by inhibiting aberrant protein aggregation, plays an important role in the regulation of various physiological functions, as well as in the development of disease. Any abnormality in this process leads to protein misfolding and aggregation, and the accumulation and aggregation of ubiquitinated proteins is a common feature of many neurodegenerative diseases, including AD. A growing number of studies have confirmed the significance of UPS in the AD process, which may act in conjunction with other mechanisms leading to the development of AD, and may even be the direct cause of AD. UPS offers a whole new possibility for the development of drugs for AD prevention and treatment, as well as new strategies and approaches for the treatment of neurodegenerative diseases. Therefore, this review is based on UPS, describes the possible mechanisms of action of UPS in AD, and summarizes the preclinical studies of modulating UPS for the treatment of AD.

Keywords:  Alzheimer’s disease; Aβ protein; tau protein; ubiquitin-proteasome system; ubiquitination

DOI:  https://doi.org/10.3389/fnagi.2025.1730206
Front Mol Biosci. 2025 ;12 1719678

Protein aggregates and biomolecular condensates: implications for human health and disease.

Ambuja Navalkar, Anoop Arunagiri, Tovaria Kee, Kathigna Panchal, Kathryn Dick.

  Biomolecular condensates are at the forefront of understanding biological concepts, representing one of the most revolutionary areas in cell biology over the last decade. Numerous proteins, peptides, and nucleic acids have been shown to form membrane-less organelles, also known as condensates, in cells, demonstrating their functional relevance. Multiple research approaches in the fields of physics, chemistry, and biophysics investigate the underlying multivalent interactions that influence the phase separation of biomolecules. As failure to regulate condensate properties, such as formation and/or dissolution has been postulated as a driver of the misfolding and aggregation of proteins in stress, aging, and neurodegeneration disorders, understanding the fundamentals of condensate assembly has been considered of utmost importance. In this review, we will focus on the key regulators and biophysical drivers of phase separation and protein aggregation, evidenced in the literature. We will elaborate on the dynamic interplay between phase separated and aggregated state, highlighting the emergent properties of condensates that can contribute to the misfolding of proteins in the context of physiology and diseases. An in-depth understanding of condensate pathology can reveal novel avenues for targeting proteinopathies linked to misfolding.

Keywords:  amyloid; biomolecular condensates; protein aggregates; protein misfolding; proteinopathies

DOI:  https://doi.org/10.3389/fmolb.2025.1719678
bioRxiv. 2025 Nov 29. pii: 2025.11.25.690488. [Epub ahead of print]

Neuronal APOE4 alone is sufficient to drive tau pathology, neurodegeneration, and neuroinflammation in an Alzheimer's disease mouse model.

Jessica Blumenfeld, Yaqiao Li, Min Joo Kim, Oscar Yip, Luokang Yao, Samuel De Leon, Rebecca Fulthorpe, David Shostak, Zoe Platow, Kaylie Suan, Yanxia Hao, Nicole Koutsodendris, Claire Ellis, Jeremy Nguyen, Yadong Huang.

Apolipoprotein E4 (APOE4), the strongest genetic risk factor for late-onset Alzheimer's disease (AD), exacerbates tau tangles, amyloid plaques, neurodegeneration, and neuroinflammation-the pathological hallmarks of AD. While astrocytes are the primary producers of APOE in the CNS, neurons increase APOE expression under stress and aging. Prior work established that neuronal APOE4 is essential for AD pathogenesis, but whether it is sufficient to drive disease remained unknown. We generated a PS19 tauopathy mouse model selectively expressing APOE4 in neurons. Neuronal APOE4 alone proved sufficient to promote pathological tau accumulation and propagation, neurodegeneration, and neuroinflammation to levels comparable to a tauopathy model with human APOE4 knocked-in globally. Single-nucleus RNA sequencing further revealed similar transcriptomic changes in neurons and glia of both models. Together, these findings demonstrate that neuronal APOE4 alone can initiate and propagate AD pathologies, underscoring its pivotal role in disease pathogenesis and its potential as a therapeutic target.

DOI: https://doi.org/10.1101/2025.11.25.690488
Mol Biol Rep. 2025 Dec 18. 53(1): 208

The role and interplay among Autophagy, Apoptosis, and ferroptosis in acute pancreatitis: mechanisms and therapeutic approaches.

Islam Ahmed Abdelmawgood, Donia Mohamed Hussien, Michael Ibrahim Boushra.

  Acute pancreatitis (AP) is a prevalent gastrointestinal condition characterized by an inflammatory response in the pancreas, with a global prevalence of 4.9-73.4 per 100,000 individuals. As the disease advances, its severity and prognosis fluctuate. Mechanisms of programmed cell death (PCD) include apoptosis, ferroptosis, and autophagy; understanding their interactions is crucial for maintaining cellular homeostasis. Each pathway represents a distinct PCD process, and current studies emphasize the complex interrelationships and reciprocal effects among them. Therefore, investigating these interactions is essential for understanding how cells determine their fate and how these mechanisms contribute to various illnesses. Increasing evidence indicates that PCD significantly contributes to the development of AP, and drugs targeting various forms of PCD constitute a possible treatment approach. Consequently, understanding the function and mechanism of PCD in AP enhances our understanding of its pathophysiological mechanisms and offers substantial benefits for the management of AP. The review's importance lies in examining the interactions among ferroptosis, apoptosis, and autophagy, with critical implications for the development of therapeutic approaches, especially in conditions characterized by dysregulated cell death. By analyzing the biochemical interactions among these pathways, scientists may identify novel drug targets and develop strategies to regulate cell fate successfully. This review examines the interplay and crosstalk among apoptosis, autophagy, and ferroptosis signaling pathways in the regulation of AP development.

Keywords:  Acute pancreatitis; Apoptosis; Autophagy; Ferroptosis; Programmed cell death

DOI:  https://doi.org/10.1007/s11033-025-11319-z
bioRxiv. 2025 Dec 14. pii: 2025.12.14.694212. [Epub ahead of print]

Differential Regulation of APOE4-Mediated Astrocytic Lipid Metabolism by BMP Signaling Exacerbates Alzheimer's Disease Pathologies in Neurons.

Anne K Linden, Amira Affaneh, Aimee Aylward, Yvette Wong, John A Kessler, Chian-Yu Peng.

The two greatest risk factors for Alzheimer's Disease (AD) are aging and Apolipoprotein E4 (APOE4) polymorphism, yet how these factors interact remain unclear. In this study, we investigate how bone morphogenetic protein (BMP) signaling, which increases with age, contributes to APOE4-induced lipid metabolic dysfunctions using induced-pluripotent stem cell (iPSC)-derived astrocytes and cocultured neurons. Surprisingly, BMP signaling differentially altered lipid droplet formation, cholesterol synthesis and breakdown, and fatty acid-oxidation in APOE4 compared to APOE3 astrocytes, and increased secretion of oxidized LDL (oxLDL). Furthermore, neurons cocultured with BMP4-treated APOE4 astrocytes showed altered transcriptomic profiles based on scRNA-seq as well as increased tau phosphorylation (p-tau). oxLDL treatment similarly increased p-tau and reduced neuronal survival. Conversely, lipid uptake inhibition in neurons rescued the BMP4/APOE4 astrocyte-induced neuronal phenotype. These data demonstrate key interactions between APOE4 and aging-associated molecular signaling in AD pathogenesis and establish a causal linkage between astrocytic lipid metabolism and neuronal tau hyperphosphorylation.

DOI: https://doi.org/10.64898/2025.12.14.694212
Ageing Res Rev. 2025 Dec 16. pii: S1568-1637(25)00344-7. [Epub ahead of print] 102998

Diapause and Aging: Two opposing yet intertwined biological phenomena.

Hamidreza Khodajou-Masouleh, Sogol Ghanbari.

  Diapause is an evolutionarily conserved strategy that enables many organisms to survive prolonged exposure to harsh environmental stressors. During this state, organisms drastically reduce their metabolic rate, halt development, and enhance stress tolerance in an energy-efficient manner. Remarkably, many diapausing organisms appear to substantially slow or suspend aging as a result of profound metabolic depression and developmental arrest. Consequently, diapause and aging appear to be programmed in opposite directions, yet both rely on many of the same master regulatory genes and epigenetic modulators. This review explores the molecular mechanisms underlying diapause-induced stress resistance and metabolic suppression, offering critical insights into how dormant biological systems preserve function and delay aging. Manipulating these shared regulatory networks has led to significant extensions in lifespan and improvements in healthspan across various model organisms. Anhydrobiotic species such as Artemia, Caenorhabditis elegans, and tardigrades can nearly suspend aging during dormancy by downregulating metabolic pathways and accumulating protective macromolecules. Notably, the African turquoise killifish, which has adapted to life in ephemeral ponds, can provide a unique platform to study both diapause and aging within a single vertebrate model. Phenotypic plasticity may offer the most compelling evolutionary explanation for resolving the paradox of how the same regulatory network can produce opposite outcomes in diapause and aging. Overall, diapause offers a powerful natural framework for uncovering anti-aging mechanisms and holds great promise for guiding the development of novel interventions to promote longevity and healthy aging.

Keywords:  Aging; Cell cycle arrest; Diapause; Epigenetic modifications; Master regulatory genes; Metabolic depression; Stress tolerance

DOI:  https://doi.org/10.1016/j.arr.2025.102998
J Biol Chem. 2025 Dec 17. pii: S0021-9258(25)02914-X. [Epub ahead of print] 111062

Age-dependent topoisomerase I depletion alters recruitment of rDNA silencing complexes.

Lindsey N Power, Natalia Zawrotna, Manikarna Dinda, Abigail E Weir, B Bishal Paudel, Oshil Ghimire, Karolina Kisiel, Christopher T Letai, Kevin A Janes, Jeffrey S Smith.

  Genomic instability and loss of proteostasis are two of the primary Hallmarks of Aging. Although these hallmarks are well-defined in the literature, the mechanisms that drive genomic instability and loss of proteostasis as cells age are still incompletely understood. Using budding yeast replicative lifespan as a model for aging in actively dividing cells, we identify nuclear proteins that are depleted in the earliest stages of aging. We find that many age-depleted proteins are involved in ribosome biogenesis, specifically in ribosome processing, or in maintenance of chromatin stability. We focus on topoisomerase I (Top1) as a novel age-depleted nuclear protein and determine that its depletion in the early stages of aging is not a result of transcriptional changes or changes in protein turnover. Despite the stark depletion of Top1 in early aging, we find that rescue of this age-dependent depletion is harmful to replicative lifespan. When overexpressed, Top1 disrupts the stoichiometry of the RENT complex by pulling Sir2 away from the ribosomal DNA (rDNA), a phenotype that is further enhanced when the overexpressed Top1 is catalytically dead. Loss of Sir2 from the rDNA via the overexpression of catalytically dead Top1 decreases RNA Pol II silencing of a reporter gene inside or adjacent to the rDNA, consistent with the lifespan defect. Finally, we show that the catalytic activity of Top1 plays an important role in the establishment of rDNA silencing, raising the possibility that rDNA secondary structure/DNA topology is important for RNA Pol I-dependent spreading of silent chromatin across the rDNA locus.

Keywords:  Proteomics; aging; rDNA; replicative lifespan; topoisomerase I; yeast

DOI:  https://doi.org/10.1016/j.jbc.2025.111062
Glia. 2026 Feb;74(2): e70112

Novel Roles for the Ectoenzyme CD38 in the Maintenance of Transcriptional and Metabolic Homeostasis in Astrocytes.

S Basak, A M Colafrancesco, R D Hernandez, X Wei, L J McMeekin, D Dang, M Simmons, J L Browning, K Noel, F Zhou, F E Lund, J S Saad, S G Watsen, A M Pickrell, R M Cowell, M L Olsen.

  CD38 is an ectoenzyme that converts NAD+ to NAM to help maintain bioenergetic homeostasis. CD38 dysregulation and gene variation is reported in neurodegenerative conditions such as Parkinson's disease (PD) and Alzheimer's disease (AD), highlighting the need to better understand CD38 biology within the brain. Here, we demonstrate enrichment of Cd38 in midbrain astrocytes and describe how CD38 deficiency influences brain metabolism, astrocytic gene expression, and bioenergetics. We demonstrate increased NAD content, decreased NAM content, and increased NAD/NAM in the midbrain and striatum of CD38-deficient (Cd38-/-) mice, indicating the dependence on CD38 for NAD to NAM conversion in the brain. RNA-sequencing of isolated astrocytes revealed numerous differentially expressed genes in Cd38+/- and Cd38-/- mice, with alterations in mitochondrial, metabolic, senescence-related, astrocyte reactivity, and other genes involved in PD and AD etiology. Furthermore, functional metabolic analysis of midbrain revealed changes in pyruvate oxidation, age-dependent increase of citrate synthase (CS) activity, and reduction of cytochrome c oxidase-to-CS ratio in Cd38 deficiency. These findings identify a novel role for astrocytes in the regulation of CD38-dependent NAD/NAM homeostasis in the brain and provide a framework for future studies evaluating the relationship between CD38 dysfunction, aging, and vulnerability of neuronal populations in neurodegenerative disease. Importantly, these studies underscore the necessity to better resolve the impact of CD38 deficiency on brain metabolism, considering ongoing clinical trials and discussions related to the use of CD38 modulators for the treatment of cancers, age-related decline, and neurodegenerative disease.

Keywords:  RNA‐sequencing; aging; astrocyte; brain metabolism; mitochondria; neurodegeneration

DOI:  https://doi.org/10.1002/glia.70112