bims-proned 2026-08-30 papers

Issue of 2026–08–30
five papers selected by
Verena Kohler, Umeå University

Front Aging Neurosci. 2026 ;18 1910154

Proteostasis breakdown and aggregate diversity in aging and neurodegenerative disease.

Protein aggregation and proteostasis decline are central features of aging and neurodegenerative disease, arising from progressive impairment of protein quality-control systems and transitions into aggregation-prone states. During aging, diverse proteins, including metabolic and proteostasis-related factors, gradually accumulate in aggregated forms as proteostasis capacity declines. Although these aggregates often remain compatible with cellular function, increasing aggregate burden progressively challenges proteostasis resilience. Neurodegenerative diseases are characterized by the emergence and amplification of highly toxic, structurally ordered protein assemblies, including amyloid-β (Aβ) and tau, which exist along a continuum with broader age-associated proteome instability rather than as entirely distinct phenomena. Oxidative and metabolic imbalances promote non-enzymatic post-translational modifications (PTMs), including cysteine oxidation, S-nitrosylation, and carbonylation, which alter protein structure, impair degradation pathways, and facilitate misfolding and aggregation. Here, we compare oxidative PTM-driven aggregates observed during aging with disease-associated protein assemblies, highlighting both shared biophysical mechanisms and distinct pathological outcomes. We propose a threshold model in which the cumulative burden of oxidative PTMs, protein misfolding, and impaired clearance progressively erodes proteostasis capacity, increasing susceptibility to the emergence of selective, self-amplifying aggregates. By integrating intracellular quality-control systems with extracellular clearance pathways, including glymphatic and meningeal lymphatic networks, this framework provides a mechanistic perspective on how aggregate diversity evolves toward disease-associated pathology and suggests therapeutic strategies that combine aggregate-specific targeting with restoration of global proteostasis and clearance capacity.

Keywords: aging; amyloid-β and tau; glymphatic system; neurodegenerative disease; protein aggregation; proteostasis

DOI: https://doi.org/10.3389/fnagi.2026.1910154

Nat Nanotechnol. 2026 Aug 28.

A self-assembled peptide forms α-helical nanopores for ultrasensitive biomarker profiling.

Varsha Shaji, Rajeev Jain, Neethu Puthumadathil, Kalyanashis Jana, Vedasmiritha T S, Ulrich Kleinekathöfer, Krishnananda Chattopadhyay, Kozhinjampara R Mahendran.

α-Helical nanopores are attractive molecular sensors, yet their rational design and assembly remain challenging. Here we show that the single peptide pPorA, derived from porin PorACj, self-assembles into flexible α-helical nanopores, inserts in lipid membranes and exists in distinct small- and large-conductance states. By strategically incorporating unnatural amino acids, we engineered small- and large-diameter pores exhibiting single-channel conductances of 2.4 nS and 3.5 nS in 1 M KCl, respectively, while retaining a common octameric architecture. These nanopores enabled the detection of sugars, peptide enantiomers and intrinsically disordered disease proteins that form dynamic, heterogeneous assemblies. The large pores detected multiple α-synuclein (α-syn) variants, including a pathogenic Parkinson's disease-associated C-terminal deletion mutant with nanomolar affinity (KD ≈ 20 nM). Selective electrostatic trapping of the α-syn N-terminus enabled charge-resolved identification of individual α-syn species within heterogeneous mixtures. The nanopores further resolved time-dependent and inhibitor-modulated α-syn aggregation pathways from monomers to toxic oligomers and fibrils. The small pores detected humanin and superoxide dismutase peptides associated with apoptosis and amyotrophic lateral sclerosis, demonstrating tunable sensing through pore-size control. These conformationally programmable α-helical nanopores provide a versatile platform for ultrasensitive profiling of disease biomarkers.

DOI: https://doi.org/10.1038/s41565-026-02265-3

ADMET DMPK. 2026 ;14 3366

Magnetoreceptive CRY/MagR complexes: linking circadian redox signalling to protein aggregation in Alzheimer's and Parkinson's disease.

Mozhgan Alipour, Behnam Hajipour-Verdom, Faria Ashrafi, Sara Rahmati Roodsari, Shabnam Nohesara, Alireza Zali, Farzad Ashrafi.

Background and purpose: Neurodegenerative disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD) pose an escalating challenge to neuroscience, as disease-modifying therapies remain elusive despite substantial advances in molecular and cellular understanding. These disorders share convergent pathological features, including protein misfolding and aggregation, mitochondrial dysfunction, oxidative stress, impaired proteostasis, and disruption of circadian regulation. Identifying integrative frameworks that connect these processes is therefore essential for advancing conceptual models of neurodegeneration. This review examines magneto-proteins, with a particular focus on CRY/MagR-based magnetoreceptor complexes, as emerging biological systems that may intersect with key molecular pathways implicated in AD and PD.
Experimental approach: We synthesized literature from neuroscience, biophysics, and circadian biology to evaluate the potential relevance of magnetoreceptor mechanisms to AD and PD pathology. We first summarized the core neuropathological mechanisms underlying both diseases, including amyloid-β and tau pathology in AD and α-synuclein aggregation and dopaminergic vulnerability in PD. We then outlined the biophysical foundations of magneto-protein function, emphasizing cryptochrome-mediated radical pair mechanisms, iron-sulphur cluster-dependent magnetic sensitivity, and their established roles in redox signalling and circadian biology.
Key results: Accumulating experimental evidence from cellular and animal models suggests that CRY/MagR-associated pathways can modulate oxidative stress, mitochondrial bioenergetics, protein aggregation dynamics, autophagic processes, and circadian control of neuronal metabolism. These processes closely overlap with molecular determinants of neuronal vulnerability in AD and PD. However, direct validation in mammalian and human systems remains limited and controversial, representing a critical knowledge gap.
Conclusion: The mechanistic convergence between magnetoreceptor biology and neurodegenerative pathology warrants critical evaluation but remains largely speculative in humans. By integrating findings across disciplines, this review positions CRY/MagR-based magneto-proteins as a conceptual platform for exploring how magnetic field-responsive molecular systems may inform our understanding of neurodegenerative disease mechanisms, while emphasizing the need for rigorous mammalian validation.

Keywords: Cryptochrome; circadian rhythms; magnetoreceptor; oxidative stress

DOI: https://doi.org/10.5599/admet.3366

Cell Death Differ. 2026 Aug 26.

G3BP1 depletion, observed in Parkinson's Disease, drives Golgi-lysosome-autophagy defects.

Sarayu Ramakrishna, Laura Ryan, Sung Min Son, David C Rubinsztein.

The RNA binding G3BP1 is depleted in several neurodegenerative diseases, yet its functional consequences at the cellular level remain poorly understood. While best known for its critical role in stress granule formation, we demonstrate that G3BP1 also stabilises the COPI vesicle protein beta-COP by promoting its interaction with the deubiquitinase USP10. G3BP1 depletion disrupts this interaction leading to increased ubiquitination of beta-COP, which accelerates its proteasomal degradation. This leads to compromised Golgi structure and function, and impaired lysosomal homeostasis, which causes defective autophagic flux. Consequently, the autophagic clearance of α-synuclein, a protein that can drive Parkinson's disease (PD), is significantly slowed. Importantly, we observe a concurrent reduction of both G3BP1 and beta-COP protein levels in brain sections from PD and dementia with Lewy Body (DLB) patients and from a PD mouse model. These findings reveal a novel mechanistic link between G3BP1, vesicular trafficking, and proteostasis in neurodegeneration.

DOI: https://doi.org/10.1038/s41418-026-01853-z

FEBS J. 2026 Aug 29.

The dual role of Rpt3 in protecting cells from proteotoxic damage.

Ziting Zhu, Xiao Feng, Boyi Song, Hongzhen Zhu, Chunyi Lv, Qiaoqiao Zheng, Siyu Pan, Zheyu Fan, Zhiwei Huang, Ping Shi.

Disrupted protein homeostasis is a shared characteristic in ageing, obesity-induced lipotoxicity and neurodegenerative diseases. The accumulation of misfolded or unfolded proteins within the cell triggers endoplasmic reticulum (ER) stress. In response, the unfolded protein response (UPR) and ER-associated degradation (ERAD) pathways are activated. A key mechanism to alleviate intracellular protein aggregation involves ubiquitination of substrates and their subsequent degradation by the proteasome. The ubiquitin-proteasome system (UPS) is indispensable for cellular protein quality control, and its dysfunction contributes to various proteopathies. However, the crosstalk between the proteasome subunit Rpt3 and the Ire1-Hac1 pathway appears to be rarely reported. In Saccharomyces cerevisiae, growth curve and spotting assay demonstrated that overexpression of Rpt3 reduced the sensitivity of ire1Δ or hac1Δ to ER stressors. The growth-promoting effect of Rpt3 is not a common feature of the BASE subunits, as overexpression of Rpt6 failed to rescue the growth inhibition. Deletion of hac1 resulted in stoichiometric imbalance among proteasomal subunits, which may be key for Rpt3-mediated rescue of hac1Δ growth, as deletion of the proteasome transcriptional factor Rpn4 impedes Rpt3 from restoring the growth of hac1Δ from ER stress. Overexpression of Rpt3 enhanced proteasome assembly and activity, reducing intracellular ubiquitin levels in hac1Δ. Moreover, Rpt3 increased the protein level of Hac1, and its alleviation of proteotoxic stress was dependent on the collaboration of ubiquitinating enzymes and chaperones. Western blot and proteasome activity assay in human cells confirmed the cross-species conservation of Rpt3 function. These results highlight a dual role for Rpt3 in proteostasis: beyond enhancing proteasomal activity, Rpt3 upregulates Hac1 protein abundance, thereby ensuring proteostasis maintenance.

Keywords: Rpt3; endoplasmic reticulum stress; proteasome; proteostasis

DOI: https://doi.org/10.1111/febs.70714