bims-proned 2026-01-18 papers

bims-proned

Biomed News

on Proteostasis in neurodegeneration

Issue of 2026–01–18
twelve papers selected by
Verena Kohler, Umeå University

Molecular Mechanisms and Therapeutic Potential of Degron-Mediated Proteostasis Regulation in Neurodegenerative Diseases.
Disulfide engineering reveals unexpected pro- and anti-aggregation conformers of human α-synuclein.
Stress Granules as a Central Hub Linking Organelle Stress, Aging, and Neurodegeneration.
Organelle dysfunction and TNT-mediated aggregate spreading in neurodegeneration.
Differential roles of proteasome and autophagy in α-synuclein and E46K oligomer clearance: insight into the modulatory effects of the dopamine metabolite DOPAC.
Insights into Mechanism of Ionic Liquids for Protein Stability: Future Implications for Neurodegeneration Treatment.
Protocol for using an ELISA assay to detect total α-synuclein levels in Drosophila melanogaster lines expressing human α-synuclein point mutations.
The interplay between autophagy and unconventional secretion in neurodegeneration.
Reduction of RAD23A extends lifespan and mitigates pathology in a mouse model of TDP-43 proteinopathy.
Revealing the conformational landscape of tau P → L mutants in R23 tau macromolecule: A pathway to targeted therapeutic design.
Investigation of Three Flavonoids as Potent Tau Aggregation Inhibitors and In vivo Demonstration of Myricetin.
Biochemical signatures of skin α-synuclein in synucleinopathies revealed by RT-QuIC assay end-product analysis.

Cell Mol Neurobiol. 2026 Jan 13.

Molecular Mechanisms and Therapeutic Potential of Degron-Mediated Proteostasis Regulation in Neurodegenerative Diseases.

D S Nishanth, Urvi Sinha, Tanishque Verma, Bharathi Kalidass, Saravana Prakash Thirumuruganandham, Gothandam Kodiveri Muthukaliannan.

  Aberrant aggregation of specific proteins-such as amyloid beta, α-synuclein, tau, TDP-43, and PrPSc-is a hallmark anomaly in the brain micro-environment, leading to a cascade of pathological events including neuroinflammation, neuronal death, cognitive impairment, and memory loss. The dysregulation in cellular protein homeostasis promotes pathological protein aggregation and hastening disease progression. Degrons are short amino acid motifs within proteins that are recognized by E3 ubiquitin ligases, which target them for degradation via the ubiquitin-proteasome system or autophagy. Recent studies emphasize that alterations in degron sequences, changes after translation or structural modifications can hinder protein homeostasis, leading to their accumulation and contributing neural toxicity. This review integrates the mechanistic role of degron with their pathological relevance and therapeutic significance in neurodegenerative diseases includes Alzheimer's disease, Parkinson's disease, Sclerosis, frontotemporal dementia, and prion diseases and further investigates the translational potential of degron-targeting techniques, including emerging biotechnological startups developing degron-based therapeutic platforms.

Keywords:  Autophagy; Degrons; Neurodegenerative diseases; Proteostasis; Ubiquitin proteosome system

DOI:  https://doi.org/10.1007/s10571-025-01659-6
bioRxiv. 2026 Jan 08. pii: 2026.01.07.698305. [Epub ahead of print]

Disulfide engineering reveals unexpected pro- and anti-aggregation conformers of human α-synuclein.

Aslam Uddin, Eugene Serebryany.

Intrinsically disordered proteins can aggregate in many distinct conformations (polymorphs). Polymorphs are a striking example of fold-switching: one primary structure able to form distinct tertiary structures. Distinct polymorphs can yield distinct molecular, cellular, and disease phenotypes. Disulfide crosslinks canalize disordered proteins into distinct regions of the conformational landscape, even if the monomer remains disordered. Human α-synuclein is a disordered, natively Cys-free protein involved in synaptic transmission. Its amyloid aggregation is implicated in Parkinson's disease and other synucleinopathies. Recent cryo-EM fibril structures have revealed distinct classes of amyloid polymorphs that wild-type human α-synuclein can adopt. We created three double-Cys α-synuclein variants predicted to form intramolecular disulfide bridges compatible with known amyloid polymorphs, plus three other double-Cys variants at arbitrary positions as controls. We purified all six variants as intramolecularly disulfide-crosslinked monomers in solution. Two of the three predicted pro-aggregation variants formed amyloid fibrils as expected, and two of the three control variants did not. Surprisingly, one of the controls formed amyloid fibrils with a distinctive morphology by negative-stain TEM, suggesting the possibility of a previously unknown polymorph. Conversely, the crosslinked variant that failed to aggregate as expected showed sub-stoichiometric, dose-dependent anti-aggregation activity, strongly suppressing amyloid formation by wild-type α-synuclein.

DOI: https://doi.org/10.64898/2026.01.07.698305
BMB Rep. 2026 Jan 12. pii: 6696. [Epub ahead of print]

Stress Granules as a Central Hub Linking Organelle Stress, Aging, and Neurodegeneration.

Hyun-Ji Ham, Jin-A Lee.

Stress granules (SGs) are dynamic cytoplasmic assemblies composed of RNAs and proteins that form in response to cellular stress, serving to halt translation and protect cellular integrity. In neurons, SGs mediate adaptive, pro-survival responses to acute stress; however, their dysregulation has been increasingly associated with both aging and neurodegenerative diseases. Aging neurons frequently exhibit changes in SG dynamics - with an increased propensity to form SGs while displaying reduced efficiency in their clearance - resulting in persistent granules that can facilitate the accumulation of pathological protein aggregates (e.g., TDP-43 or tau). Aberrant SG formation and defective clearance mechanisms are implicated in the pathogenesis of key neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Alzheimer's disease (AD), and Parkinson's disease (PD). Recent findings have shown that SGs interface with organelles such as lysosomes, mitochondria, and the endoplasmic reticulum, utilizing autophagic and other protein quality-control mechanisms for clearance. As these clearance pathways progressively decline with age, SGs can transition from promoting cellular adaptation to contributing to cellular dysfunction. In this mini-review, we examine how aging influences SG biology, detail the role of SGs in neurodegenerative diseases, and discuss emerging mechanistic insights and therapeutic strategies aimed at modulating SG dynamics in the context of brain aging.
Physiology (Bethesda). 2026 Jan 16.

Organelle dysfunction and TNT-mediated aggregate spreading in neurodegeneration.

Valentine Thomas, Chiara Zurzolo.

  Organelle dysfunction is a central hallmark of neurodegenerative diseases (NDs), which are characterized by the pathological accumulation of misfolded proteins capable of inducing aggregation in healthy cells. This process generates a self-perpetuating cycle of protein misfolding and spreading across interconnected neuronal networks. In this review, we provide an integrated overview of organelle alterations associated with major NDs, emphasizing the pivotal roles of lysosomes, mitochondria, and the endoplasmic reticulum (ER) at the crossroads of proteostasis, metabolism, and stress signaling. We examine how defects in these organelles create conditions that favor aggregate formation and cellular vulnerability, with a focus on α-synuclein and Tau, the main aggregating proteins in Parkinson's and Alzheimer's diseases, respectively. We then explore mechanisms of intercellular protein transfer, highlighting the emerging role of tunneling nanotubes (TNTs). We discuss how organelle status influences TNT formation and cargo selection, and how TNTs may act as conduits for the propagation of pathogenic aggregates. Finally, we summarize the downstream consequences of TNT-mediated transfer in recipient cells, including alterations in the autophagy-lysosomal pathway, TFEB-dependent transcription, mitochondrial stress responses, calcium homeostasis, and inflammatory or senescent signaling. Together, these insights underscore the intertwined roles of organelle dysfunction and TNT-mediated communication in driving the progression of NDs and suggest new therapeutic avenues aimed at restoring organelle function and limiting aggregate spread.

Keywords:  neurodegeneration; organelle dysfunction; protein aggregates; tunneling nanotubes

DOI:  https://doi.org/10.1152/physiol.00048.2025
Int J Biol Macromol. 2026 Jan 13. pii: S0141-8130(26)00150-9. [Epub ahead of print] 150224

Differential roles of proteasome and autophagy in α-synuclein and E46K oligomer clearance: insight into the modulatory effects of the dopamine metabolite DOPAC.

Manuela Leri, Philipp Trolese, Ilenia Inciardi, Patrizia Polverino de Laureto, Monica Bucciantini.

  The build-up of misfolded α-synuclein (Syn) proteins plays a key role in diseases such as Parkinson's disease. Here, we compared the cytotoxicity and intracellular processing of wild-type and E46K mutant Syn aggregates in SH-SY5Y neuroblastoma cells and investigated the modulatory effects of the dopamine metabolite, 3,4-dihydroxyphenylacetic acid (DOPAC). E46K aggregates displayed markedly higher toxicity than wild-type counterparts, promoting mitochondrial dysfunction and elevated reactive oxygen species (ROS) production in a time-dependent manner. This effect is consistent with the mutation's higher affinity for cellular membranes, which fosters early and sustained aggregate-membrane interactions. Strikingly, co-incubation with DOPAC during aggregation significantly reduced both toxicity and oxidative stress in wild-type and E46K aggregates. DOPAC shifted Syn into less fibrillogenic conformations, favouring smaller oligomers that were less membrane-active and more effectively processed by cellular clearance systems. Mechanistic studies revealed that E46K/DOPAC aggregates were preferentially degraded via the ubiquitin-proteasome system (UPS), as proteasome inhibition with MG132 enhanced toxicity and intracellular accumulation. In contrast, autophagy inhibition by chloroquine paradoxically reduced toxicity, indicating redirection toward UPS-mediated degradation. Analysis of lysosomal markers showed that DOPAC-containing aggregates colocalized with LAMP1 but not LAMP2A, suggesting processing through macroautophagy rather than chaperone-mediated autophagy. Furthermore, p62 accumulation, indicative of impaired autophagic flux, was evident with untreated aggregates but absent when DOPAC was present. Overall, our results demonstrate that DOPAC reshapes the biophysical and toxicological properties of Syn aggregates, especially E46K species, by promoting less harmful oligomers and enhancing proteostatic clearance. These findings highlight DOPAC as a promising modulator of Syn aggregation and pathology.

Keywords:  DOPAC; E46K mutation; Proteasome degradation; macroautophagy; α-Synuclein

DOI:  https://doi.org/10.1016/j.ijbiomac.2026.150224
Ageing Res Rev. 2026 Jan 08. pii: S1568-1637(26)00016-4. [Epub ahead of print] 103024

Insights into Mechanism of Ionic Liquids for Protein Stability: Future Implications for Neurodegeneration Treatment.

Kajal Sharma, Mohammad Shahid, Rajan Patel, Asimul Islam.

  Neurodegenerative diseases are characterized by a gradual loss of neurons, cellular dysfunction, loss of intricate synaptic networks and brain damage, which are going to be the second leading cause of death in future. These proteinopathies are marked by abnormal amyloid fibril deposition, aberrant aggregation of misfolded proteins via polymerization, where protein aggregates serve as key pathological hallmarks in Alzheimer's, Parkinson's, and multiple system atrophy disorders. These toxic aggregates accumulate in the brain and disrupt neuronal function targeting motor neurons, spinal cord, and ultimately leading to respiratory failure and death. As population age, the prevalence of these neuronal disorders rises significantly, emphasizing to approach effective treatment for risk reduction. In the pursuit of developing effective anti-amyloidogenesis therapeutic agents, ionic liquids (ILs) continue to receive least attention. ILs have emerged as promising substitute for conventional solvents, owing to their unique physicochemical properties that facilitate protein refolding, mitigate denaturation, amyloidogenesis, and prevent aggregation. This review critically addresses intricate IL-protein interactions, dictated by anions-cations composition of ILs, their polarity, hydrophobicity, kosmotropicity, chaotropicity, amphiphillicity, and network, which modulate protein behavior and support structural and functional integrity. This article also underscores the need for precision in IL selection, ensuring their properties align with the desired structural outcome. We showcase ILs as a promising therapeutic avenue for neurodegenerative diseases, demonstrating their potential to modulate pathological protein aggregation and enhance protein homeostasis. Lastly, this review of outstanding research works, account for current lacunae that will guide future perspectives for the rational designing of IL for protein stabilization and offers new strategies for addressing underlying mechanism of ageing disorders.

Keywords:  Aggregate dissolution; Amyloids fibrils; Co-solvent; Ionic liquids; Neurodegenerative diseases; Protein stabilization

DOI:  https://doi.org/10.1016/j.arr.2026.103024
bioRxiv. 2026 Jan 07. pii: 2026.01.07.698009. [Epub ahead of print]

Protocol for using an ELISA assay to detect total α-synuclein levels in Drosophila melanogaster lines expressing human α-synuclein point mutations.

Marco Sciortino, Raquel Velazquez, Haven Tillmon, Swati Banerjee.

In Parkinson's disease (PD), alpha-synuclein (α-syn) aggregation causes neuronal dysfunction and death, particularly of dopaminergic neurons, which is central to PD symptoms and progression. This protocol describes the use of a sandwich ELISA assay to quantify total α-syn levels in various Drosophila melanogaster genotypes expressing human α-syn point mutations associated with PD. Utilizing this protocol allows for the precise quantification of total α-syn levels in the Drosophila melanogaster (fly) model.

DOI: https://doi.org/10.64898/2026.01.07.698009
Cell Chem Biol. 2026 Jan 15. pii: S2451-9456(25)00400-3. [Epub ahead of print]33(1): 10-32

The interplay between autophagy and unconventional secretion in neurodegeneration.

Maurizio Renna, Raffaella Bonavita, Grace Dixon, Luigi Vittorio Verdicchio, Angeleen Fleming.

  Within neurons, the misfolding and aggregation of certain proteins has been identified as a common feature of many late-onset neurodegenerative diseases (NDs). These aggregate-prone proteins include tau (in both primary tauopathies and in Alzheimer's disease) and alpha-synuclein in Parkinson's disease. There is strong experimental evidence that the upregulation of intracellular clearance pathways (autophagy and ubiquitin-proteasome pathways) can clear aggregate-prone proteins in experimental models. When the flux through these pathways is increased, the levels of aggregate-prone proteins are reduced, resulting in improved cell survival in both cell-based and animal models of ND. More recently, a third strategy for clearing proteins from cells has been identified, via the unconventional secretion of proteins out of the cell. However, secretion may also facilitate the spreading and propagation of disease through a prion-like process. This review explains how the autophagy and unconventional secretion pathways interact and how these impact ND.

Keywords:  alpha-synuclein; autophagy; extracellular vesicles; neurodegeneration; secretory autophagy; tau; unconventional protein secretion

DOI:  https://doi.org/10.1016/j.chembiol.2025.12.007
Nat Commun. 2026 Jan 16.

Reduction of RAD23A extends lifespan and mitigates pathology in a mouse model of TDP-43 proteinopathy.

Xueshui Guo, Ravindra Singh Prajapati, Jiyeon Chun, Insuk Byun, Kamil K Gebis, Yi-Zhi Wang, Karen Ling, Casey Dalton, Jeff A Blair, Anahid Hamidianjahromi, Gemma Bachmann, Frank Rigo, Paymaan Jafar-Nejad, Jeffrey N Savas, Min Jae Lee, Jemeen Sreedharan, Robert G Kalb.

Protein misfolding and aggregation are cardinal features of neurodegenerative disease (NDD) and they contribute to pathophysiology by both loss-of-function (LOF) and gain-of-function (GOF) mechanisms. This is well exemplified by TDP-43 which aggregates and mislocalizes in several NDDs. The depletion of nuclear TDP-43 leads to reduction in its normal function in RNA metabolism and the cytoplasmic accumulation of TDP-43 leads to aberrant protein homeostasis. A modifier screen found that loss of rad23 suppressed TDP-43 pathology in invertebrate and tissue culture models. Here we show in the TAR4 mouse model of TDP-43 pathology that genetic or antisense oligonucleotide (ASO)-mediated reduction of rad23a confers benefits on survival and behavior, histological hallmarks of disease and reduction of mislocalized and aggregated TDP-43. This results in improved function of the ubiquitin-proteasome system (UPS) and correction of transcriptomic alterations evoked by pathologic TDP-43. RAD23A-dependent remodeling of the insoluble proteome appears to be a key event driving pathology in this model. As TDP-43 pathology is prevalent in both familial and sporadic NDD, targeting RAD23A may have therapeutic potential.

DOI: https://doi.org/10.1038/s41467-025-65104-4
Int J Biol Macromol. 2026 Jan 08. pii: S0141-8130(25)10590-4. [Epub ahead of print] 150033

Revealing the conformational landscape of tau P → L mutants in R23 tau macromolecule: A pathway to targeted therapeutic design.

Hao Li, Hyundong Kim, Myounwoo Kim, Jin Yong Lee.

  Misfolding of the microtubule-associated protein tau is central to the pathology of several neurodegenerative disorders, including Alzheimer's disease, Pick's disease, and progressive supranuclear palsy. Although proline-to-leucine (P → L) substitutions in tau are known to accelerate aggregation, the molecular mechanisms underlying this effect-and potential strategies to counter it-remain incompletely understood. Here, we use replica-exchange molecular dynamics (REMD) to investigate how single (P301L, P332L) and double (P2L) P → L mutations in tau's R23 fragment reshape its conformational landscape. Our simulations reveal that single mutations substantially elevate β-sheet content (by up to 17% compared to wild-type) and increase aggregation propensity. Paradoxically, the double mutant reduces β-sheet formation and enhances α-helical structure, effectively curtailing aggregation. Contact map and hydrogen-bond analysis confirm that introducing the second P → L substitution reorganizes intrachain interactions in a way that mitigates misfolding. These findings advance our fundamental understanding of tau aggregation and suggest a counter-intuitive therapeutic concept: engineering an additional mutation may stabilize tau more effectively than merely suppressing a pathogenic mutation. We propose integrative next steps-virtual screens, AI clustering, and ssNMR-to guide translation.

Keywords:  Aggregation; Neurodegeneration; P → L mutation; Replica-exchange molecular dynamics; Tau protein

DOI:  https://doi.org/10.1016/j.ijbiomac.2025.150033
Pharmacol Res Nat Prod. 2025 Dec;pii: 100449. [Epub ahead of print]9

Investigation of Three Flavonoids as Potent Tau Aggregation Inhibitors and In vivo Demonstration of Myricetin.

Bogdan M Benin, Trae Hillyer, Bovinari A Csubak, Noah Aguirre, Christine M Dengler-Crish, Chounghun Kang, Woo Shik Shin.

  Neurodegenerative disorders, including Alzheimer's disease (AD), are characterized by the formation and propagation of neurotoxic tau aggregates, which arise from the misfolding and subsequent aggregation of tau proteins into fibrillary structures. While tau-targeting agents represent a promising therapeutic strategy for the prevention and treatment of various neurodegenerative diseases, they currently constitute a limited subset of the treatments undergoing clinical trials. In this study, we report the potent anti-aggregation and filament disassembly effects of three flavonols: myricetin, quercetagetin, gossypetin. We observed remarkable nanomolar-to-low-micromolar 50% inhibitory concentrations (0.57-1.21μM) and low 50% disassembly concentrations (7.5-14μM) using tau seeds derived from AD mouse model brains. Furthermore, we validated that myricetin treatment was associated with a reduction in overall phosphorylated tau (p-Tau) burden in vivo in the 3xTg AD mouse model. Notably, these reductions were associated with enhanced performance in Y-maze assessments of spatial learning and memory, supporting further preclinical evaluation, including direct brain pharmacokinetic studies and mechanism-driven investigations relevant to tauopathy therapy.

Keywords:  Flavonoids; Myricetin; Tau; tau Disassembler; tau inhibitor

DOI:  https://doi.org/10.1016/j.prenap.2025.100449
Acta Neuropathol. 2026 Jan 12. 151(1): 3

Biochemical signatures of skin α-synuclein in synucleinopathies revealed by RT-QuIC assay end-product analysis.

Maria Gerasimenko, Hancun Yi, Tricia Gilliland, Yijia Chen, Zerui Wang, Wen-Quan Zou.

  Synucleinopathies, including Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA), share pathological accumulation of misfolded α-synuclein (αSyn) in the brain and overlapping clinical features, complicating accurate diagnosis with current methods. In this study, we utilized a real-time quaking-induced conversion (RT-QuIC) assay to demonstrate that autopsied skin samples from PD, DLB, and MSA patients (but not non-synucleinopathy controls) seed aggregation of recombinant αSyn. While RT-QuIC generated similarly positive fluorescence kinetic curves across synucleinopathies, biochemical and morphological analyses of RT-QuIC end products revealed distinct properties in the resulting αSyn aggregates. Notably, αSyn aggregates from DLB samples exhibited the highest resistance to proteinase K digestion, whereas MSA-derived aggregates showed the least aggregated bands on Western blots. Transmission electron microscopy revealed significant differences in length, width, and volume of skin αSyn fibrils of RT-QuIC end products from different synucleinopathies. These findings provide critical insights into disease-specific αSyn structural characteristics and suggest new strategies to improve diagnostic discrimination.

Keywords:  Dementia of Lewy body; Multiple system atrophy; Parkinson’s disease; RT-QuIC; Skin; Synucleinopathy; α-Synuclein

DOI:  https://doi.org/10.1007/s00401-025-02973-5