bims-proned 2026-09-13 papers

bims-proned

Biomed News

on Proteostasis in neurodegeneration

Issue of 2026–09–13
twelve papers selected by
Verena Kohler, Umeå University

When Pathologies Collide: The Intersection of Tau and Alpha-Synuclein in Neurodegenerative Diseases.
Advances in phytochemical modulation of protein aggregation in neurodegenerative diseases.
From Glycation to Toxicity: α-Synuclein Oligomers, Oxidative Stress, and Multi-Targeted Protection by Trans-Ferulic Acid.
Cellular modifiers of TDP-43 phase transition and cytoplasmic aggregation.
Cross-disease protein aggregate interactions in neurodegeneration: from molecular mechanisms to therapeutic strategies.
A Site-Specific Organometallic Approach for Installing Tyrosine Phosphorylation Mimics to Decipher the Role of Phosphorylation in α-Synuclein Aggregation and Seeding.
Protein aggregation as a bistable switch in bacterial cell fate: from adaptive dormancy to cytotoxic death.
The VHL tumor suppressor at the crossroad of protein folding, aggregation, and cancer.
Neurotoxic mechanisms of cadmium in neurodegenerative diseases.
Mitochondrial NMNAT3 reduces amyloid aggregates in Drosophila and alters the amyloid processing in the 3xTgAD mouse.
SIRT1 in Neurodegenerative Diseases: Molecular Mechanisms, Disease Relevance, and Therapeutic Potential.
Detection of α-synuclein seeding activity in tear fluid as a candidate biomarker for Parkinson's disease.

Mol Neurobiol. 2026 Sep 08. pii: 882. [Epub ahead of print]63(1):

When Pathologies Collide: The Intersection of Tau and Alpha-Synuclein in Neurodegenerative Diseases.

Jenna N Hunt, Sandhya Kortagere.

  Neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD), are becoming increasingly prevalent in today's aging population and with significant cost to society. While these diseases were traditionally defined by distinct protein aggregates, namely, tau tangles and amyloid-β (Aβ) plaques in AD and α-synuclein (α-syn) inclusions in PD, substantial evidence reveals frequent mixed pathologies, with tau, α-syn, and Aβ aggregates coexisting in patients. This copathology complicates understanding disease mechanisms, classification, and progression, highlighting the need to examine mixed pathologies in neurodegenerative diseases to develop disease-modifying therapies. The presence of mixed proteinopathies suggests shared or converging pathological mechanisms, including synergistic aggregation, enhanced seeding capabilities, and shared protein-protein interactions. Understanding these molecular mechanisms is essential for identifying disease modifiers and refining experimental models. This review explores the pathogenic mechanisms of α-syn and tau individually, followed by exploration of their molecular interactions and potential mechanisms of coaggregation and exacerbation of pathology. By recognizing the intersection of these pathologies, further research can refine disease classifications for neurodegenerative diseases.

Keywords:  Mixed proteinopathies; Neurodegenerative diseases; Parkinson’s disease; Synuclein; Synucleinopathy; Tau

DOI:  https://doi.org/10.1007/s12035-026-06163-6
3 Biotech. 2026 Oct;16(10): 416

Advances in phytochemical modulation of protein aggregation in neurodegenerative diseases.

Nitu Kumari, Santosh Anand.

  Protein aggregation and misfolding are central pathological events underlying major neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, and related proteinopathies. The aberrant aggregation of amyloid-β, tau, and α-synuclein generates toxic oligomeric and fibrillar species that disrupt proteostasis, impair synaptic function, promote oxidative stress and neuroinflammation, and ultimately drive progressive neuronal loss. This review critically summarizes recent advances in plant-derived secondary metabolites with anti-aggregation properties, emphasizing their structural diversity, molecular mechanisms, structure-activity relationships, and translational potential. Current findings demonstrate that polyphenols, flavonoids, terpenoids, alkaloids, curcuminoids, and secoiridoids inhibit protein aggregation through multiple complementary mechanisms, including direct modulation of amyloidogenic proteins and restoration of proteostasis via molecular chaperones, the ubiquitin-proteasome system, autophagy-lysosomal pathways, mitochondrial protection, and suppression of neuroinflammatory signaling. Emerging evidence further demonstrates that rational structural optimization, hybrid molecule design, and nanotechnology-based delivery systems can substantially improve the pharmacokinetic limitations of these compounds. Overall, the accumulated evidence indicates that phytochemicals possess multitarget therapeutic potential by simultaneously reducing protein aggregation, oxidative stress, mitochondrial dysfunction, and neuroinflammation, thereby offering broader neuroprotection than single-target approaches. Nevertheless, limited bioavailability, poor blood-brain barrier penetration, interspecies variability, and insufficient clinical validation continue to impede translation. By integrating mechanistic evidence with recent advances in medicinal chemistry and drug delivery, this review highlights promising strategies to accelerate the development of phytochemical-based therapeutics for protein aggregation-associated neurodegenerative diseases. Unlike previous studies that primarily summarize anti-amyloid phytochemicals, this review integrates recent mechanistic insights into protein aggregation, proteostasis regulation, medicinal chemistry optimization, structural biology, and translational challenges across multiple neurodegenerative proteinopathies.

Keywords:  Amyloid-β; Neurodegeneration; Phytochemicals; Polyphenols; Protein aggregation; α-Synuclein

DOI:  https://doi.org/10.1007/s13205-026-05046-w
Cell Biochem Biophys. 2026 Sep 08.

From Glycation to Toxicity: α-Synuclein Oligomers, Oxidative Stress, and Multi-Targeted Protection by Trans-Ferulic Acid.

Murtaza Hussain, Md Nadir Hassan, Rizwan Ahmad, Gul E Zehra, Amrit Kaur, Umme Kulsum Baliyavi, Tariq Aziz, Rizwan Hasan Khan, Waseem Ahmad Siddiqui.

  Glycation, a spontaneous reaction between sugars and biomolecules, is a central driver of oxidative stress and protein dysfunction in metabolic and neurodegenerative disorders. α-Synuclein (α-Syn), a key protein implicated in Parkinson's disease, is particularly susceptible to modification by reactive carbonyl species such as methylglyoxal (Me) due to its lysine-rich structure. These modifications result in the formation of advanced glycation end products (AGEs), which promote protein aggregation, impair cellular clearance, and induce oxidative and inflammatory damage via the AGE-RAGE axis. This cascade, characterised by increased reactive oxygen and nitrogen species, mitochondrial dysfunction, and metabolic imbalance, accelerates neuronal degeneration and disease progression.This study investigates trans-ferulic acid (TF) as a multifunctional therapeutic candidate targeting this interconnected network. TF effectively inhibited glycation in both ribose and Me-induced α-Syn systems, demonstrating strong antiglycation potential. Additionally, TF exhibited significant scavenging activity against hydrogen peroxide and nitric oxide, underscoring its capacity to reduce oxidative and nitrosative stress. TF also inhibited α-glucosidase, indicating a further mechanism for controlling glucose availability and limiting the formation of reactive intermediates. Collectively, these findings identify TF as a promising multi-target agent capable of disrupting the glycation-oxidative stress cycle at multiple levels. By concurrently reducing reactive species, suppressing carbonyl formation, and limiting protein aggregation, TF represents a compelling strategy to mitigate glycation-driven toxicity and its pathological consequences.

Keywords:  Advanced glycated end products (AGEs); Glycation; Oxidative stress; Protein misfolding

DOI:  https://doi.org/10.1007/s12013-026-02150-9
Elife. 2026 Sep 08. pii: RP110172. [Epub ahead of print]15

Cellular modifiers of TDP-43 phase transition and cytoplasmic aggregation.

Natalie Chin, Qi Zhang, Jizhong Zou, Ken Chih-Chien Cheng, Wei Zheng, Yihong Ye.

  RNA-binding protein TAR DNA-binding protein 43 (TDP-43) can form liquid-like nuclear assemblies whose phase behavior is thought to influence its aggregation propensity and neurotoxic activity. The mechanisms that govern the liquid-to-solid phase transition of TDP-43 remain poorly defined. Here, we combined chemical and genome-wide genetic screens to identify cellular factors that modulate the phase behavior of an RNA-binding-defective TDP-43 mutant. Our screens uncovered multiple cellular processes, including RNA splicing, protein translation, proteostasis imbalance, and nuclear export as TDP-43 phase regulators. We also developed a semi-permeabilized cell system that partially recapitulates the TDP-43 phase transition in vitro, and showed that nuclear export inhibition reshapes the nuclear environment to favor RNA-dependent liquid-liquid phase separation (LLPS) of TDP-43, which mitigates its aggregation. Nuclear export inhibition in a brain organoid model bearing an ALS-associated mutation reduces pathogenic phospho-TDP-43 accumulation. These findings identify multiple modulators of TDP-43 phase transitions in a sensitized model system and establish a framework for further dissecting the link between nuclear transport and TDP-43 phase dynamics.

Keywords:  TDP-43; XPO1; cell biology; human; liquid-liquid phase separation; protein aggregation

DOI:  https://doi.org/10.7554/eLife.110172
Neurol Sci. 2026 Sep 08. pii: 764. [Epub ahead of print]47(10):

Cross-disease protein aggregate interactions in neurodegeneration: from molecular mechanisms to therapeutic strategies.

Wenqi Yang, Yan Lu.

   BACKGROUND: Neurodegenerative diseases have traditionally been classified by their predominant protein pathology. However, accumulating evidence reveals extensive molecular cross-talk between distinct pathological proteins, particularly in Alzheimer's disease (AD).
OBJECTIVE: This review examines cross-disease protein interactions and their implications for diagnosis and treatment.
METHODS: We systematically reviewed peer-reviewed literature published between 2020 and 2025, complemented by seminal earlier studies, examining molecular mechanisms of protein cross-seeding, clinical evidence of co-pathology, and emerging therapeutic strategies.
RESULTS: Cross-seeding between amyloid-β (Aβ), tau, α-synuclein, and TDP-43 has been demonstrated in vitro and in vivo. Harmonized autopsy studies reveal that 91% of individuals over 80 years harbor multiple neuropathologies. Co-pathology accelerates cognitive decline and complicates biomarker interpretation. Anti-amyloid immunotherapies lecanemab and donanemab demonstrate 27-35% slowing of cognitive decline, while anti-tau antibodies targeting N-terminal epitopes have uniformly failed, prompting investigation of combination approaches.
CONCLUSIONS: Recognition of cross-disease protein interactions necessitates a paradigm shift toward multi-target therapeutic strategies and precision medicine approaches accounting for individual co-pathology burden.

Keywords:  Alzheimer's disease; Amyloid-β; Cross-seeding; Immunotherapy; Neurodegeneration; TDP-43; Tau; α-Synuclein

DOI:  https://doi.org/10.1007/s10072-026-09364-y
J Am Chem Soc. 2026 09 02. 148(34): 37286-37297

A Site-Specific Organometallic Approach for Installing Tyrosine Phosphorylation Mimics to Decipher the Role of Phosphorylation in α-Synuclein Aggregation and Seeding.

Shaswati Mandal, Xiaoxi Lin, Anastasia V Gemelli, Manjeet Singh, Anne-Laure Mahul-Mellier, Yllza Jasiqi, Bouchra Bouri, Muhammad Jbara, Hilal A Lashuel.

Several studies have identified phosphorylation of α-synuclein (aSyn) at multiple tyrosine residues (Y39, Y125, Y133, and Y136) within Lewy bodies (LB), which are the pathological hallmarks of Parkinson's disease (PD). However, understanding the specific role of phosphorylation at each site, or how multiple phosphorylation sites interact, has been challenging. Herein, we present an efficient method that leverages an organometallic Pd-complex to site-specifically attach phosphomimetic groups via Cys-arylation, closely mimicking natural phosphorylation. Using this approach, we successfully incorporated native-like tyrosine phosphorylation mimics into cysteine-containing proteins like synthetic transcription factor Max and recombinant aSyn, in good yields. To demonstrate the method's versatility, we created a focused library of mono-, di-, and triphosphorylated aSyn analogues. This development enabled, for the first time, the investigation of the effect of site-specific phosphorylation at multiple C-terminal tyrosine residues on aSyn fibrillization and aggregation. Our results show that monophosphorylation at any of the C-terminal sites has little effect on aggregation, while di- and triphosphorylation slows down the process, extending the lag phase compared to wild-type aSyn. Additionally, phosphorylation at Y39 reduces the seeding activity of aSyn fibrils by almost 2-4-fold in both mammalian and neuronal models of synuclein pathology. Overall, our strategy provides a rapid, selective, and scalable way to introduce aromatic PTMs, producing homogeneous protein libraries essential for mechanistic studies, biomarker development, and exploring the therapeutic potential of targeting aSyn-phosphorylation for PD and related disorders.

DOI: https://doi.org/10.1021/jacs.6c12345
Front Microbiol. 2026 ;17 1929318

Protein aggregation as a bistable switch in bacterial cell fate: from adaptive dormancy to cytotoxic death.

Yuejuan Nong, Weijie Wang, Weiwei Zhu.

  Protein aggregation has traditionally been considered a hallmark of proteostasis disruption and cellular dysfunction. However, recent studies have revealed that bacterial protein aggregation is not merely a passive consequence of stress-induced damage but may represent a dynamic component of cellular adaptation. Under adverse conditions, reversible protein condensation and aggregation have been associated with bacterial dormancy, persistence, and the viable but non-culturable (VBNC) state, whereas excessive and irreversible aggregation may contribute to loss of cellular function and bacterial death. Nevertheless, whether protein aggregation serves as a primary determinant of bacterial cell fate or reflects a consequence of broader physiological changes remains an important unresolved question. In this review, we summarize current advances in understanding bacterial protein aggregation, including the roles of liquid-liquid phase separation (LLPS), protein quality control systems, ATP-dependent proteostasis regulation, and aggregate maturation. We discuss how stress-induced alterations in proteostasis networks influence bacterial survival, aging, persistence, and antibiotic tolerance. Available evidence supports a working model whereby the physicochemical properties of protein aggregates may dictate ultimate bacterial cell fate. Nevertheless, the causal link between condensate phase behavior, aggregate material characteristics, and cell fate decisions remains to be thoroughly validated, even though emerging technologies including live single-molecule cell imaging and quantitative analytical tools have greatly advanced our mechanistic understanding of the dynamic progression of bacterial protein aggregation. Finally, we discuss the therapeutic potential and challenges of targeting bacterial proteostasis and aggregation pathways to combat persistent and multidrug-resistant pathogens. A deeper mechanistic understanding of how protein aggregation balances adaptation and toxicity may reveal new vulnerabilities within bacterial survival strategies.

Keywords:  bacterial aging; bacterial dormancy; bacterial proteostasis; cell death; protein aggregation; stress response

DOI:  https://doi.org/10.3389/fmicb.2026.1929318
Mol Oncol. 2026 Sep 07.

The VHL tumor suppressor at the crossroad of protein folding, aggregation, and cancer.

Lara Abad, Silvio Carlo Ermanno Tosatto, Emanuela Leonardi.

  Protein aggregation is no longer viewed only as pathological but as a dynamic and reversible regulatory mechanism in cancer. Within the tumor microenvironment, proteins such as the von Hippel-Lindau tumor suppressor protein (pVHL) can transition from a folded state to aggregated states. Mutations, environmental stress, and dysfunctional chaperone systems further promote pVHL aggregation. Structural plasticity enables adaptive responses that support protein storage, cell survival, and dormancy, a reversible state promoting drug resistance and cancer recurrence. Targeting protein aggregation with chemical chaperones and amyloid inhibitors could represent a promising therapeutic strategy to rescue the tumor suppressor activity and overcome dormancy-associated drug resistance. In this review, we address the amyloid aggregation of pVHL, the factors contributing to this behavior, the correlation between protein aggregation and cellular dormancy, and potential therapeutic strategies that bridge protein aggregation and oncology.

Keywords:  amyloid‐targeted therapy; cancer dormancy; protein aggregation; von Hippel–Lindau

DOI:  https://doi.org/10.1002/1878-0261.70325
Front Cell Dev Biol. 2026 ;14 1899381

Neurotoxic mechanisms of cadmium in neurodegenerative diseases.

Zihao Zhang, Yutao Lu, Jiawei Yang, Meiren Li, Mingliu Yang, Yanhao Xu, Muhammad Saad Ullah, Qing Wan, Bing Bao, Wenmin Yu, Xiaoqun Liu.

  Cadmium (Cd) is a highly toxic, bioaccumulative heavy metal increasingly implicated in the pathogenesis of neurodegenerative disorders. This review systemically characterizes the molecular mechanisms underlying Cd-induced neurotoxicity, with particular emphasis on oxidative stress-mediated pathways that initiate interconnected processes including ferroptosis, mitochondrial impairment, disruption of calcium homeostasis, and chronic neuroinflammation. Evidence indicates that Cd exerts both convergent and disease-specific effects in neurodegenerative conditions. In Alzheimer's disease (AD), Cd exposure has been associated with enhanced amyloid-β (Aβ) deposition and increased tau hyperphosphorylation. In Parkinson's disease (PD), Cd disrupts metabolic homeostasis via the gut-liver-brain axis and promotes aberrant conformational changes and aggregation of α-synuclein (α-Syn). Within the amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD) spectrum, Cd contributes to TDP-43 proteinopathy and impairs nucleocytoplasmic transport mechanisms. Therapeutic strategies targeting Cd-induced neurotoxicity are also explored, including upstream approaches like metal chelation and downstream interventions aimed at restoring autophagic flux, modulating the neuroimmune microenvironment, and enhancing neuronal repair. Although emerging platforms such as brain organoids provide valuable mechanistic insights, translating findings from in vitro models to real-world chronic exposure scenarios remains a significant challenge. This review provides a comprehensive framework for the development of early-warning systems and precision-based interventions for Cd-related neurodegeneration.

Keywords:  cadmium; ferroptosis; inflammation; neurodegenerative diseases; neurotoxicity; oxidative stress

DOI:  https://doi.org/10.3389/fcell.2026.1899381
Mitochondrial Commun. 2026 ;4 1-9

Mitochondrial NMNAT3 reduces amyloid aggregates in Drosophila and alters the amyloid processing in the 3xTgAD mouse.

Zhu Yi, Naynika Juvvadi, Grace Zhai, Carlos T Moraes, Milena Pinto.

Alzheimer's disease is a progressive neurological disorder characterized by two main neuropathological hallmarks: neurofibrillary tangles and amyloid plaques. Both are protein aggregates, composed mainly of hyperphosphorylated Tau and the amyloid fragment Aβ, respectively. NMNAT (Nicotinamide mononucleotide adenylyltransferase) is an endogenous enzyme involved in the conversion of NMN to NAD. It is known for its neuroprotective functions, particularly against axonal degeneration. We have previously shown that different isoforms of NMNAT can protect cells from neurotoxic stress caused by protein aggregates by acting as chaperones. Accordingly, the mitochondrial-localized isoform NMNAT3 exhibits potent chaperone activity, which antagonizes the aggregation of a wide spectrum of pathological amyloid client proteins in culture, including Tau and amyloid beta. Although mostly cytosolic, Aβ has also been detected in mitochondria and mitochondrial membranes. To investigate whether NMNAT3 could serve as a neuroprotective factor in amyloid pathology in vivo, we overexpressed NMNAT3 in two different models: a Drosophila model overexpressing APP and PS1 in developing photoreceptors, and the 3xTg-AD mouse, in which NMNAT3 was expressed in forebrain neurons and which accumulates neurofibrillary tangles and plaques in the hippocampus and cortex. When expressed in the Drosophila eye, APP accumulated in a location- and time-dependent manner, and co-expression of NMNAT3 decreased the total number of aggregates. When expressed in the mouse brain, NMNAT3 did not affect amyloid plaque number or volume; nonetheless, it altered APP processing, leading to the accumulation of oligomers and soluble C-terminal fragments. We conclude that the effects of NMNAT3 on APP differ between models, likely due to differences in access to the sites of protein aggregation and the neuronal environments between flies and mice.

DOI: https://doi.org/10.1016/j.mitoco.2026.01.001
FASEB J. 2026 Sep 15. 40(17): e72288

SIRT1 in Neurodegenerative Diseases: Molecular Mechanisms, Disease Relevance, and Therapeutic Potential.

Jiabin Duan, Jiaqi Liu, Qingsheng Meng, Jiahao Liu, Sitian Yang, Fang Zhou, Jing Cao.

  Neurodegenerative diseases are characterized by progressive protein aggregation, mitochondrial dysfunction, neuroinflammation, and cognitive decline, yet effective mechanism-based interventions remain limited. Sirtuin 1 (SIRT1), an NAD+-dependent deacetylase, has emerged as a multifunctional regulator linking stress adaptation, proteostasis, and metabolic homeostasis to disease progression. Increasing evidence indicates that SIRT1 supports cognitive resilience by coordinating synaptic plasticity, autophagy-lysosomal function, mitochondrial homeostasis, and inflammatory control. In Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD), reduced or dysregulated SIRT1 is associated with protein aggregation, mitochondrial dysfunction, and cognitive decline, although its effects may be disease- and stage-dependent, particularly in HD. This review summarizes the structural and catalytic features of SIRT1, examines the mechanisms linking SIRT1 to cognitive impairment across major neurodegenerative diseases, and evaluates the opportunities and limitations of SIRT1-targeted therapeutic strategies.

Keywords:  SIRT1; mitochondrial dysfunction; neurodegenerative diseases; neuroinflammation; proteostasis; therapeutics

DOI:  https://doi.org/10.1096/fj.202602361RR
J Parkinsons Dis. 2026 Sep 07. 1877718X261486736

Detection of α-synuclein seeding activity in tear fluid as a candidate biomarker for Parkinson's disease.

Asako Kakimoto, Katsuya Satoh, Tomoko Tsukahara-Kawamura, Yoshio Tsuboi.

  BackgroundParkinson's disease (PD) is an α-synucleinopathy, and pathological α-synuclein (α-Syn) is detectable in peripheral tissues and fluids. However, the diagnostic utility of tear fluid as a minimally invasive source for α-Syn seed detection remains unclear. We aimed to detect α-Syn seeds in tear fluid and evaluate the clinical characteristics of α-Syn-positive patients.MethodsTear fluid was collected bilaterally using Schirmer strips. The α-Syn seeding amplification assay (αSynSAA) was performed using the real-time quaking-induced conversion (RT-QuIC) protocol. We analyzed 55 patients with PD and 40 control participants.ResultsThe αSynSAA revealed α- synuclein seeding activity in tear fluid, showing 52.7% sensitivity and 100% specificity. αSyn SAA-positive patients had higher Movement Disorder Society-Unified Parkinsons Disease Rating Scale part III scores than αSyn SAA-negative patients. α-Syn seeding activity was detected in tear fluid from some patients with PD but not in disease controls.ConclusionThis study demonstrates the feasibility of αSynSAA analysis in tear fluid, highlighting its potential as a novel substrate for biomarker development. Further studies in related synucleinopathies and in early or prodromal PD are needed to validate these findings and assess the diagnostic performance of this tear-based assay.

Keywords:  Parkinson's disease; RT-QuIC; tear biomarkers; tear fluid; α-Syn seeding amplification assays (αSynSAA); α-synuclein (α-Syn)

DOI:  https://doi.org/10.1177/1877718X261486736