bims-proned 2026-02-08 papers

bims-proned

Biomed News

on Proteostasis in neurodegeneration

Issue of 2026–02–08
fourteen papers selected by
Verena Kohler, Umeå University

FUS and TDP-43 aggregation are uncoupled from toxicity in ageing yeast models.
Dual-action strategy to reprogram chaperone activity for α-synuclein aggregate clearance in Parkinson's disease.
Chemical Strategies to Modulate Amyloidogenesis Associated with Neurodegenerative Diseases.
Recent advances in small molecules for amyloid fibril inhibition: chemical strategies and molecular mechanistic insights from lysozyme and insulin models.
TDP-43 in neurodegeneration and cancer: Decoding the mechanism of mRNA localization and translation.
Quantifying the Acute Toxicity of Alpha-Synuclein Membrane-Accumulation in a Cell-Based Assay.
Native-state dimerization drives misfolding and aggregation of Cys-depleted variants of cataract-associated human lens γD-crystallin.
The endoplasmic reticulum displays high polarity with low protein aggregation in human cells.
Proteostasis of organelles in aging and disease.
Optimization of α-Synuclein and Tau Detection by Immunoblot in Enteroendocrine Cell Lines.
Spatial organization of ER-derived protein aggregates in the nucleus requires the Hsp70-family member BiP.
HSP-1-Specific Nanobodies Alter Chaperone Function in vitro and in vivo.
Heat Shock Proteins in Neurodegenerative Diseases.
mRNA translation and proteasomal degradation in health and neurological disease.

BMC Biol. 2026 Feb 06.

FUS and TDP-43 aggregation are uncoupled from toxicity in ageing yeast models.

Donovan W McDonald, Nikita Chugh, Rares Sava, Martin L Duennwald.

   BACKGROUND: Protein aggregation is indicative of the loss of proteostasis associated with neurodegenerative diseases, including Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD). Proteins like Fused in sarcoma (FUS) and Tar DNA-binding protein 43 (TDP-43) accumulate and aggregate in the cytosol of neurons in ALS/FTD. Yet, it remains unclear how ageing affects FUS and TDP-43 aggregation, and how these aggregates in turn influence neurodegeneration in ALS/FTD. In addition, mistranslation can reduce longevity, challenge proteostasis, and modulate protein aggregation. To investigate how ageing and mistranslation modulate FUS and TDP-43 aggregation and toxicity, we enlist tractable and reliable yeast models.
RESULTS: Using optimized low-expression FUS and TDP-43 yeast models, we demonstrate that chronological ageing antagonizes proteostasis, the steady state levels and solubility of molecular chaperones, and aggregation of FUS and TDP-43. In addition, mistranslation caused by tRNA variants further antagonize FUS and TDP-43 aggregation and synergize to exacerbate FUS and TDP-43 cytotoxicity.
CONCLUSIONS: Our work provides new insights into factors that uncouple FUS and TDP-43 aggregation from toxicity and support a rather protective role for FUS and TDP-43 aggregates in promoting longevity.

Keywords:  ALS; Ageing; FUS; Mistranslation; Mitochondria; Molecular chaperone; Protein aggregation; Protein misfolding; TDP-43

DOI:  https://doi.org/10.1186/s12915-026-02537-3
Int J Biol Macromol. 2026 Feb 04. pii: S0141-8130(26)00656-2. [Epub ahead of print] 150730

Dual-action strategy to reprogram chaperone activity for α-synuclein aggregate clearance in Parkinson's disease.

Oliwia Koszła, Przemysław Sołek, Joanna Depciuch, Maciej Maj.

  Parkinson's disease, a progressive neurodegenerative disorder, is characterized by the accumulation of toxic α-synuclein aggregates. Molecular chaperones, key to homeostasis, offer a promising mechanism for the clearance of misfolded proteins. Here, we investigated a novel therapeutic approach combining the natural compound resveratrol and lithium chloride in an in vitro model of Parkinson's disease using human LUHMES cells challenged with pre-formed α-synuclein fibrils (PFF). The impact of mono- and co-treatment on α-synuclein levels, aggregation, cell viability, metabolic activity, oxidative stress, aggresome formation, and chaperone activation was assessed. FTIR spectroscopy was employed to analyze cellular biochemical profiles. Our findings demonstrate that the co-treatment of resveratrol and lithium chloride elicits a potent combination effect, significantly reducing both unphosphorylated and phosphorylated α-synuclein levels and decreasing the formation of aggresomes. Notably, this combined treatment robustly activated the cellular molecular chaperone system, a key mechanism for protein quality control. Furthermore, the co-therapy protected cellular viability and maintained metabolic activity, without exacerbating oxidative stress. Biochemical profiling using FTIR spectroscopy further supported the beneficial impact of the co-treatment, indicating a trend towards the restoration of normal cellular molecular signatures. These results underscore the unique and promising potential of combining resveratrol and lithium chloride as a supplementary therapeutic strategy for Parkinson's disease, leveraging their enhanced action to enhance the clearance of neurotoxic α-synuclein aggregates.

Keywords:  Fibrils; Lithium chloride; Misfolding protein; Molecular chaperones; Protein quality control; Resveratrol; α-Synuclein

DOI:  https://doi.org/10.1016/j.ijbiomac.2026.150730
ACS Appl Mater Interfaces. 2026 Feb 04.

Chemical Strategies to Modulate Amyloidogenesis Associated with Neurodegenerative Diseases.

Chanju Na, Youngeun Jang, Mikyung Son, Mi Hee Lim.

  Amyloidogenic peptides and proteins, including amyloid-β, tau, and α-synuclein, are key pathological factors in neurodegenerative diseases. Their misfolding and self-assembly into toxic oligomers and fibrils disrupt cellular homeostasis and lead to neuronal dysfunction. To address these pathogenic processes, diverse chemical strategies have been developed employing nanomaterials, small organic molecules, and metal complexes. These reagents chemically modify amyloidogenic peptides and proteins, thereby altering their aggregation pathways, attenuating associated toxicity, and demonstrating in vivo efficacy. In this review, we outline and discuss the design principles and mechanistic bases of these chemical interventions, with some examples that demonstrate anti-amyloidogenic effects. Collectively, these advances underscore the power of chemistry to modulate amyloid aggregation and provide mechanistic insights that can guide the development of innovative therapeutic strategies for amyloid-driven neurodegeneration.

Keywords:  anti-amyloidogenic activity; chemical peptide and protein modifications; metal complexes; nanomaterials; neurodegenerative disorders; small organic molecules

DOI:  https://doi.org/10.1021/acsami.5c20362
Bioorg Chem. 2026 Jan 27. pii: S0045-2068(26)00075-1. [Epub ahead of print]171 109539

Recent advances in small molecules for amyloid fibril inhibition: chemical strategies and molecular mechanistic insights from lysozyme and insulin models.

Venkatramanan Kumar, Mariya Tom, R M Santhosini, Reeshma Begam, S Jayashree, S M Jaimohan.

  Protein misfolding and aggregation are central pathological processes underlying amyloidosis, a group of disorders characterized by the deposition of insoluble amyloid fibrils. These toxic aggregates form due to conformational destabilization and exposure of hydrophobic protein regions, leading to aberrant interactions that disrupt normal cellular functions. Amyloid fibrillation is a key pathological event in both neurodegenerative and systemic disorders. In metabolic and systemic amyloidosis, such as lysozyme derived and insulin derived amyloidosis, peripheral fibril deposition leads to progressive organ dysfunction, while cerebral amyloid accumulation is associated with neurodegenerative diseases like Alzheimer's. To inhibit protein aggregation and destabilize preformed fibrils, a wide range of amyloid inhibitors has been explored. While naturally derived molecules offer some anti-amyloid activity, their limitations have driven growing interest in synthetic and semi-synthetic organic molecules, repurposed drugs, organic dyes, and short peptides. These agents offer enhanced chemical versatility, improved biocompatibility, and the ability to modulate multiple stages of amyloid aggregation. This review provides an overview of the molecular mechanisms of protein misfolding and recent advances in the molecular design, structure-activity relationships, and evaluation of synthetic and semi-synthetic amyloid inhibitors. Using lysozyme and insulin as model systems, we highlight emerging strategies for anti-amyloidogenic intervention.

Keywords:  Amyloid aggregation; Insulin; Lysozyme; Protein misfolding and fibrillation; Small synthetic molecule inhibitors; neurodegenerative and systemic amyloidosis

DOI:  https://doi.org/10.1016/j.bioorg.2026.109539
Biochem Biophys Rep. 2026 Mar;45 102464

TDP-43 in neurodegeneration and cancer: Decoding the mechanism of mRNA localization and translation.

Panjiao Pang, Mingyang Yu, Huixin Ma, Longkai Wei, Jiali Huang, Lingxin Zhao, Ying-Hua Zhang.

  The localization and translation of mRNAs play crucial roles in maintaining cellular phenotype and function, with RNA-binding protein (RBP) contributing significantly to these processes. TAR DNA-binding protein of 43 kDa (TDP-43) is an RNA/DNA-binding protein that is primarily localized in the nucleus, where it performs essential functions in pre-mRNA splicing, mRNA transport, and the stabilization and localized translation of mRNA. Its mis-localization from the cytoplasm, as well as mutations, protein misfolding, and posttranslational modifications, is closely linked to a reduction in its RNA-binding ability. This functional impairment is implicated in the initiation and progression of neurodegenerative diseases and cancer. In this review, we begin with a retrospective analysis of the molecular mechanism by which distinct domains of TDP-43 contribute to the initiation and progression of disease, particularly because its overexpression in tumors significantly influences disease progression. We subsequently elucidate the classical mechanisms of mRNA localization and translation, while clarifying the role of TDP-43 in these processes. Finally, we summarize the mechanisms by which TDP-43 facilitates the formation of ribonucleoprotein particles and this protein's involvement in mRNA localization and translation, as well as its associated molecular pathways. In conclusion, this review highlights the critical roles of TDP-43 and subsequent therapeutic strategies for treatment of neurodegenerative diseases and tumors.

Keywords:  Liquid-liquid phase separation; Local translation; Molecular mechanism; Protein aggregation; TDP-43; mRNA localization

DOI:  https://doi.org/10.1016/j.bbrep.2026.102464
Res Sq. 2026 Jan 21. pii: rs.3.rs-8576084. [Epub ahead of print]

Quantifying the Acute Toxicity of Alpha-Synuclein Membrane-Accumulation in a Cell-Based Assay.

Baoyi Li, Amirah K Anderson, Oren A Levy, Nagendran Ramalingam, Ulf Dettmer.

Parkinson's disease (PD) is a progressive neurodegenerative disorder that affects over 12 million people worldwide. A central pathological feature is the accumulation of aggregated alpha-synuclein (αS) in Lewy bodies and Lewy neurites. Engineered αS variants such as 3K (E35K + E46K + E61K) and KLK (KTKEGV→KLKEGV in 6 repeats) have been shown to enhance membrane binding and aggregation propensity, contributing to cellular toxicity. To further investigate the impact of 3K and KLK on αS biology, we developed a sensitive assay in a human neuroblastoma model to assess expression levels and cytotoxicity. Relative to wild-type αS, the 3K mutant exhibited reduced steady-state expression and increased toxicity, consistent with prior reports. In contrast, the KLK mutant showed no marked change in protein expression but induced significantly higher toxicity, more than the 3K variant. These findings underscore the utility of our assay in dissecting disease-relevant mechanisms and highlight the potential of engineered αS variants to model pathogenic features of PD. This platform offers a versatile tool for evaluating therapeutic strategies targeting αS aggregation and toxicity in PD and related synucleinopathies.

DOI: https://doi.org/10.21203/rs.3.rs-8576084/v1
bioRxiv. 2025 Dec 29. pii: 2025.12.29.696901. [Epub ahead of print]

Native-state dimerization drives misfolding and aggregation of Cys-depleted variants of cataract-associated human lens γD-crystallin.

Yu Pu, Vanie Seecharan, Loy Hashimoto, Aslam Uddin, Eugene Serebryany.

Cataract, the leading cause of blindness worldwide, results from age-related misfolding and aggregation of long-lived crystallin proteins in the eye lens. The cytoplasm of fiber cells in the lens core becomes increasingly oxidizing with age, allowing non-native disulfides to drive light-scattering aggregation of γ-crystallins. Despite this vulnerability to non-native disulfides, and despite lacking any native-state disulfides, γ-crystallins are unexpectedly Cys-rich. To understand this paradox, we investigated how replacing all four Cys residues in the aggregation-prone N-terminal domain of γD-crystallin affects its stability and aggregation. Cys removal precludes the disulfide-driven aggregation pathway we reported previously. Here, we characterize two full-length human γD-crystallin variants: C18S/C32S/C41S/C78S ("NCS") and C18T/C32A/C41A/C78A ("NCA/T"). Thermodynamic and kinetic stability measurements indicate the N-terminal domain was greatly destabilized in both variants relative to WT, with NCS more destabilized than NCA/T. Upon mild heating or partial denaturation, both variants formed light-scattering aggregates, which were amorphous by transmission electron microscopy. Surprisingly, the aggregation proceeded exclusively from a native-state dimer held together by a C-terminal disulfide bridge. Aggregation was strongly suppressed by the lens's native chemical chaperone, myo -inositol. The aggregation rate depended linearly on protein concentration, indicating that the rate limiting step was a transformation of the native-state dimer to a misfolded dimer. The native-state dimer forms readily even in the WT protein, and evidence of it has been found in the lens. We propose that many age-related chemical modifications could destabilize the native fold of human γD-crystallin, favor misfolding within its native-state dimer, and thereby cause aggregation.

DOI: https://doi.org/10.64898/2025.12.29.696901
Commun Biol. 2026 Feb 03.

The endoplasmic reticulum displays high polarity with low protein aggregation in human cells.

Xinwei Hu, Junlin Chen, Ping Liu, Huaiyue Zhang, Yu Liu, Xin Zhang, Lei Wang.

Many physicochemical properties in the cellular milieu are important for cell function and survival. However, the polarity of different subcellular compartments and its role in protein condensate and aggregate formation within cells are less characterized. Here, we develop a method to compare the polarity in different subcellular compartments using the same polarity-sensitive solvatochromic fluorescent probe. Unexpectedly, the endoplasmic reticulum (ER) lumen displays a higher polarity and a more crowded environment than the cytosol in human cells. Polarity-decreasing and crowding-increasing hypertonic conditions induce condensate or aggregate formation of two intrinsically disordered proteins, with-no-lysine kinase 1 and Huntingtin gene (Htt) exon1 with an expanded polyQ stretch (Htt-polyQ), in the cytosol. However, targeting Htt-polyQ to the ER prevents its aggregation, suggesting that polarity but not crowding is more relevant to protein aggregation. Our results reveal the heterogeneity in subcellular polarity and crowding, and uncover previously unrecognized high-polarity in the ER lumen, which provides a unique environment for maintaining robust proteostasis.

DOI: https://doi.org/10.1038/s42003-025-09491-w
FEBS J. 2026 Feb 04.

Proteostasis of organelles in aging and disease.

Yara Nabawi, Cansu Doğan, Dunja Petrović, Gülce Perçin, Seda Koyuncu, David Vilchez.

  To maintain proteome integrity within distinct subcellular compartments, cells rely on tightly regulated proteostasis mechanisms, including protein synthesis, folding, trafficking, and degradation. Disruption of these processes leads to the accumulation of damaged proteins and structural changes that progressively compromise organelle function, contributing to aging and age-associated disorders, such as neurodegeneration, cancer, and metabolic dysfunction. Here, we discuss recent insights into how proteostasis influences the integrity and function of specific organelles, including the nucleus, mitochondria, endoplasmic reticulum, Golgi apparatus, and lysosomes, as well as membraneless organelles, such as stress granules, processing bodies, the nucleolus, and nuclear speckles. We further discuss how dysfunction in these systems contributes to different hallmarks of aging and disease progression, highlighting potential therapeutic strategies aimed at maintaining organelle homeostasis to promote healthy aging.

Keywords:  aging; cellular stress responses; membraneless organelles; membrane‐bound organelles; neurodegenerative diseases; organelle dysfunction; protein aggregation; proteostasis; stress granules

DOI:  https://doi.org/10.1111/febs.70439
Neurogastroenterol Motil. 2026 Feb;38(2): e70259

Optimization of α-Synuclein and Tau Detection by Immunoblot in Enteroendocrine Cell Lines.

Giuseppe Madaro, Pierre-François Charbonneau, Thibauld Oullier, Michel Neunlist, Gwenola Le Dréan, Pascal Derkinderen.

   BACKGROUND: Enteroendocrine cells (EECs) are dispersed along the intestinal mucosa and transduce luminal stimuli into hormonal signals. EECs exhibit neuron-like features and express both α-synuclein and tau, two proteins pathologically and genetically linked to Parkinson disease (PD). These observations support the hypothesis that EECs may be involved in disease development in the "body-first" PD subtype. Cellular models represent invaluable tools for studying the role of α-synuclein and tau in PD pathogenesis. However, the sensitivity and specificity of commercial antibodies for detecting α-synuclein and tau in EEC cell lines remain unclear.
METHODS: We tested by immunoblot a panel of commercial total-α-synuclein and total-tau antibodies on protein lysates from three EEC cell lines: GLUTag, NCI-H716, and STC-1. Pharmacological and biochemical manipulations were applied to assess the specificity of antibodies against phosphorylated α-synuclein and tau.
KEY RESULTS: Five antibodies detected total α-synuclein in NCI-H716 lysates, whereas the antibodies D1M9X and Tau12 detected total tau in GLUTag and NCI-H716 lysates, respectively. α-synuclein and tau protein levels were comparable between naïve and differentiated NCI-H716 cells. Four phospho-specific antibodies revealed phospho-α-synuclein S129 in NCI-H716. Of the nine phospho-tau antibodies tested, six recognized tau phosphorylated at specific epitopes (T181, S199, T231, S356, S396, and S404) in GLUTag cells.
CONCLUSIONS AND INFERENCES: Our results indicate that NCI-H716 cells represent an ideal EEC model for studying α-synuclein expression and phosphorylation, whereas GLUTag cells are preferable for investigating tau protein biology. This work provides a comprehensive antibody toolbox to dissect the physiological and pathological role of α-synuclein and tau in EECs.

Keywords:  alpha‐synuclein; antibodies; enteroendocrine cells; immunoblotting; phosphorylation; tau

DOI:  https://doi.org/10.1111/nmo.70259
Biochem Biophys Res Commun. 2026 Feb 04. pii: S0006-291X(26)00170-1. [Epub ahead of print]805 153406

Spatial organization of ER-derived protein aggregates in the nucleus requires the Hsp70-family member BiP.

Shoukang Du, Yuhan Wang, Ting Gang Chew.

  Cells maintain proteostasis by sequestering misfolded proteins into deposition sites. Aggregation-prone endoplasmic reticulum (ER) proteins form membrane-bound nuclear compartments that are cleared during cell division, yet the mechanisms underlying their spatial organization remain unclear. Here, using transcriptomic and proteomic analyses, we identified the ER-localized Hsp70 chaperone BiP as a key player. Genetic depletion or chemical inhibition of BiP prevented nuclear aggregate formation, while manipulating BiP regulators perturbed the aggregate formation. BiP-driven aggregation precedes the inner nuclear membrane synthesis that encapsulated the aggregates. Under proteostatic stress, nuclear aggregates localized adjacent to ER-derived aggregates. Our findings demonstrate that BiP is essential for organizing ER-derived aggregates in the nucleus, which further regulate nuclear proteostasis through spatial interactions with nuclear aggregates.

Keywords:  BiP; Endoplasmic reticulum; Nucleus; Protein aggregates; Proteostasis

DOI:  https://doi.org/10.1016/j.bbrc.2026.153406
J Biol Chem. 2026 Feb 04. pii: S0021-9258(26)00108-0. [Epub ahead of print] 111238

HSP-1-Specific Nanobodies Alter Chaperone Function in vitro and in vivo.

Nicholas D Urban, Kunal Gharat, Zachary J Mattiola, Ashley Scheutzow, Adam Klaiss, Sarah Tabler, Asa W Huffaker, Monique Grootveld, Mary E Skinner, Weiyang Zheng, Matthew J O'Meara, Janine Kirstein, Matthias C Truttmann.

Targeted regulation of 70 kilodalton Heat Shock Protein (HSP70) chaperones, particularly the essential cognate heat shock protein (HSC70) and its Caenorhabditis elegans ortholog (HSP-1), may hold the key to improving cellular proteostasis and ameliorating aging-associated conditions linked to protein misfolding and aggregation. However, tools to selectively alter HSP70 chaperone activity remain elusive. In this study, we pioneer the development of two novel nanobodies, B12 and H5, which specifically bind to both recombinant and endogenous HSP-1. We show that these nanobodies, differing by only two amino acids in their complementarity-determining regions, bind specifically to HSP-1 and effectively reduce both HSP-1 ATPase activity and protein folding capacity in a dose-dependent manner in vitro. We further demonstrate in vivo expression of B12, but not H5, in transgenic C. elegans strains reduces heat-stress survival and proteotoxic-stress resistance, mirroring the effects of hsp-1 knockdown via RNA interference. Our findings suggest that these nanobodies can serve as effective and specific tools for inhibiting HSP-1 chaperone activity in vivo. These discoveries provide a foundation for future research exploring the therapeutic potential of HSP70-targeting nanobodies in aging and protein misfolding diseases.

DOI: https://doi.org/10.1016/j.jbc.2026.111238
Aging Dis. 2026 Jan 16.

Heat Shock Proteins in Neurodegenerative Diseases.

En Ying Yap, Duan Lu Hou, Tuchen Guan, Xiao-Xue Dong, Li Zeng, Laurie H Sanders, Yun-Cheng Wu, Eng King Tan, Zhi Dong Zhou.

Neurodegenerative diseases (NDs), which affect millions globally, are characterized by progressive motor and non-motor deficits and currently lack a cure. Molecular chaperones, particularly heat shock proteins (HSPs), have emerged as promising therapeutic candidates to combat these conditions. HSPs are classified into six major families and have been extensively studied in contexts ranging from autoimmune diseases to cancer and viral infections. Their broad functional repertoire-which includes preventing protein aggregation, correcting misfolding, regulating apoptosis, mediating autophagy, and maintaining proteostasis-positions them as potent modulators of the pathological processes underlying NDs. This review will explore the mechanisms of different HSP classes and critically assess their therapeutic potential for NDs.

DOI: https://doi.org/10.14336/AD.2025.1309
Physiology (Bethesda). 2026 Feb 05.

mRNA translation and proteasomal degradation in health and neurological disease.

Alinny R Isaac, Danielle Cozachenco, Beatriz de A Wagner, Mariana G Chauvet, Mychael V Lourenco.

  The homeostasis of cellular proteins, i.e., proteostasis, is critical for neuronal function and brain processes. Proteostasis comprises a set of cellular mechanisms that control protein synthesis, folding, post-translational modification and degradation. Mounting evidence indicates that disruptions in such mechanisms may underlie several neurological diseases, including neurodevelopmental, neurodegenerative and psychiatric diseases. In this review, we discuss molecular pathways involved in protein synthesis and degradation that are altered in several brain diseases, possible pharmacological approaches to correct these defects, and future perspectives for the field.

Keywords:  mental health; neurodegenerative diseases; proteostasis; translational control

DOI:  https://doi.org/10.1152/physiol.00023.2025