bims-proned 2026-01-11 papers

bims-proned

Biomed News

on Proteostasis in neurodegeneration

Issue of 2026–01–11
twelve papers selected by
Verena Kohler, Umeå University

When Proteins Go MAD-Misfolded, Amplified, Detected: Advances in α-Synuclein Pathophysiology and RT-QuIC Detection.
Vaccines mimicking conformational epitopes on α-synuclein fibrils provide immunity to Parkinson's disease.
Sulfate reducing bacteria induce α-synuclein in intestinal and neuronal cells and tissues and inhibit tyrosine hydroxylase in neuronal cells.
Proteasomal Degradation of Mutant Huntingtin Exon1 Regulates Autophagy.
H+ Ions and ATP Reshape the Conformational Landscape of an RNA Recognition Motif and Regulate Its Fibrillation.
Residue-Specific Modulation of Aggregation-Associated Interactions by Spermine in Tau, α-Synuclein, and Aβ40.
Neuroprotective activity of mung bean (Vigna radiata) coat extract via AMPK-dependent autophagy in Alzheimer's and Parkinson's models.
Prevention of ubiquitination at K6 and K9 in mutant huntingtin exacerbates disease pathology in a knock-in mouse model.
cGAS-STING activation in Parkinson's Disease: From mechanisms to Disease-Modifying therapeutic strategies.
Rsp5/NEDD4 and ESCRT regulate TDP-43 toxicity and turnover via an endolysosomal clearance mechanism.
Therapeutic targets in diabetic peripheral neuropathy: heat shock proteins.
MicroRNAs and Long Non-Coding RNAs Affect the Mechanisms Involved in Age-Related Neurodegeneration in a Manner Depending on RNA-Binding Proteins.

Mol Neurobiol. 2026 Jan 09. 63(1): 352

When Proteins Go MAD-Misfolded, Amplified, Detected: Advances in α-Synuclein Pathophysiology and RT-QuIC Detection.

Naďa Labajová, Adam Polák, Ondrej Cehlár, Pavle Križan, Jozef Hritz, Martin Kolisek, Matej Škorvánek, Rostislav Škrabana, Branislav Kovačech, Norbert Žilka.

  Α-Synuclein (α-Syn) aggregation and fibrillation are pathological hallmarks of several neurodegenerative disorders, collectively termed synucleinopathies. The misfolded α-Syn protein exhibits a prion-like seeding behavior, promoting misfolding, intracellular spread, and progressive neurodegeneration. Recent advances in structural biology have revealed critical insights into the conformational heterogeneity of α-Syn aggregates and their strain-specific properties across distinct synucleinopathies. In parallel, significant progress has been made in biomarker development, particularly with the arrival of seed amplification assays. Among these, Real-Time Quaking-Induced Conversion (RT-QuIC) has emerged as a highly sensitive, specific, and scalable method for detecting pathogenic α-Syn species in cerebrospinal fluid and other tissues. This review summarizes the latest findings from structural studies on α-Syn oligomers and aggregates, their relevance to disease mechanisms, and highlights RT-QuIC as the most clinically advanced and rapidly evolving assay. We discuss its potential for early, biomarker-driven diagnostics, patient stratification, and clinical implementation.

Keywords:  Aggregation; Neurodegeneration; Parkinson’s disease; RT-QuIC; Synucleinopathies; α-Synuclein

DOI:  https://doi.org/10.1007/s12035-025-05600-2
Brain. 2026 Jan 09. pii: awag010. [Epub ahead of print]

Vaccines mimicking conformational epitopes on α-synuclein fibrils provide immunity to Parkinson's disease.

Liang Ma, Sara Reithofer, Verena Pesch, José Miguel Flores-Fernandez, Aishwarya Sriraman, Caleb Duckering, Sara Amidian, Pelin Özdüzenciler, Laura Müller, Holger Wille, Gültekin Tamgüney.

  The progressive age-related aggregation of soluble α-synuclein into toxic oligomers and insoluble amyloid fibrils causes Parkinson's disease, Lewy body dementia, and multiple system atrophy, which are all neurodegenerative diseases without a cure. Because α-synuclein is a self-antigen, pathogenic α-synuclein aggregates do not elicit a strong immune response. Recent advances in structural biology elucidating the structure of α-synuclein fibrils have allowed us to design engineered protein fibrils that model conformational epitopes present on the surface of α-synuclein fibrils. HET-s is a soluble fungal protein capable of forming amyloid fibrils. We used HET-s(218-298) fibrils and four modified derivatives, each displaying a selected conformational epitope present on the surface of α-synuclein fibrils, to vaccinate TgM83+/- mice, a model for Parkinson's disease-like synucleinopathies. Fibrillar vaccine candidates significantly extended the survival of immunized TgM83+/- mice by up to 38% after intraperitoneal challenge and 42% after intragastric challenge with α-synuclein fibrils. Fully immunized mice had developed antibodies that recognized α-synuclein fibrils and brain homogenates from patients with dementia with Lewy bodies, multiple system atrophy, and Parkinson's disease. Fibrillar vaccine candidates that mimic conformational epitopes on the surface of pathological α-synuclein fibrils have the ability to induce immunity and protection against Parkinson's disease and other synucleinopathies.

Keywords:  alpha-synuclein; amyloid; conformation; disease; fibril; immunization; vaccine

DOI:  https://doi.org/10.1093/brain/awag010
Front Neurosci. 2025 ;19 1672793

Sulfate reducing bacteria induce α-synuclein in intestinal and neuronal cells and tissues and inhibit tyrosine hydroxylase in neuronal cells.

Sudha B Singh, Arianne J Capacio, Cody A Braun, Amanda Carroll-Portillo, Sephira Ryman, Henry C Lin.

   Introduction: Parkinson's disease (PD), a synucleopathy characterized by the presence of α-synuclein (α-syn) aggregates in the brain, is thought to originate in the intestine. Desulfovibrio, resident gut sulfate reducing bacteria (SRB), usually found in very low numbers in a healthy gut, are found in higher numbers in PD. In a recent study, a separate group demonstrated that Desulfovibrio isolated from both PD patients and healthy subjects were fed to C. elegans and were found to increase α-syn aggregates in the head region of the worms. How these bacteria induce α-syn aggregates in the brain through the gut remain unknown. We tested whether Desulfovibrio induced α-syn aggregates in the intestinal cells and triggered α-syn secretion from these cells into the growth medium and whether this growth medium (devoid of bacteria) further induced α-syn aggregates in neurons. We also tested whether Desulfovibrio directly induced α-syn aggregates in neuronal cells and inhibited protein expression of tyrosine hydroxylase (TH), a key dopamine-producing enzyme. We also tested whether Desulfovibrio increased α-syn levels in intestine, plasma, and in brain in mice.
Methods: Enteroendocrine STC-1 and neuronal SH-Sy5y cells were infected with Desulfovibrio vulgaris (DSV). We measured α-syn aggregation by immunofluorescence. α-syn levels in cell culture supernatant (sup), tissues, and plasma were measured by enzyme-linked immunosorbent assay (ELISA). Protein expression of TH and α-syn was analyzed by Western blot.
Results: We found that DSV increased the number of STC-1cells with α-syn aggregates and also induced α-syn expression in these cells. Sup from DSV-infected STC-1 had higher α-syn levels compared to control uninfected sup and could induce α-syn aggregates in SH-Sy5y. DSV also directly induced a syn aggregates and inhibited TH in SH-Sy5y. DSV-gavaged mice had higher levels of α-syn in the duodenum, plasma, and in brain and also showed a decreasing trend in TH expression in the brain.
Conclusion: Thus, our findings provide a gut-to-brain link tied to the ability of SRB in the gut-to increase expression, aggregation and spread of α-syn and decrease of TH in PD.

Keywords:  Desulfovibrio vulgaris (DSV); Parkinson’s disease; sulfate reducing bacteria; tyrosine hydroxylase; α-synuclein (α-syn)

DOI:  https://doi.org/10.3389/fnins.2025.1672793
Cells. 2025 Dec 30. pii: 68. [Epub ahead of print]15(1):

Proteasomal Degradation of Mutant Huntingtin Exon1 Regulates Autophagy.

Austin Folger, Chuan Chen, Phasin Gonzalez, Sophia L Owutey, Yanchang Wang.

  Accumulation of misfolded proteins is implicated in neurodegenerative diseases. One of these is Huntington's disease, which is caused by an expansion of trinucleotide (CAG) repeats in exon 1 of huntingtin gene (HTT). This expansion results in the production of mutant huntingtin exon1 protein (mHttEx1) containing polyglutamine tracks that is prone to cytotoxic aggregation. These mHttEx1 aggregates range from small soluble aggregates to large insoluble inclusion bodies. The mechanisms to clear mHttEx1 aggregates include ubiquitin-dependent proteasomal degradation and autophagy. For the proteasomal degradation of mHttEx1, ubiquitinated protein is first recognized by the Cdc48 complex for extraction and unfolding. For autophagy, mHttEx1 inclusion bodies are engulfed by an autophagosome, which fuses with the vacuole/lysosome and delivers cargo for vacuolar degradation. We name this autophagy IBophagy. In this study, we further show that the ubiquitination of mHttEx1 by the E3 ligase San1, its extraction and unfolding by the Cdc48 complex, and subsequent proteasomal degradation are all essential steps for mHttEx1 IBophagy in budding yeast, revealing a new layer of autophagy regulation and mHttEx1 cytotoxicity.

Keywords:  Cdc48 complex; IBophagy; autophagy; misfolded proteins; mutant huntingtin exon1 (mHttEx1); proteasome

DOI:  https://doi.org/10.3390/cells15010068
J Am Chem Soc. 2026 Jan 08.

H+ Ions and ATP Reshape the Conformational Landscape of an RNA Recognition Motif and Regulate Its Fibrillation.

Osama Aazmi, Akshit Rajendra Aswale, Jeetender Chugh.

Proteins exist as dynamic ensembles, with their native states comprising interconverting conformational substates critical to their physiological functions and participation in disease states. Fused in sarcoma (FUS), an RNA-binding protein implicated in neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), contains an RNA recognition motif (RRM) known to form fibrillar aggregates. Here, we investigate the conformational plasticity of FUS-RRM in its native state using advanced NMR techniques, particularly 15N chemical exchange saturation transfer and heteronuclear adiabatic relaxation dispersion experiments, to capture slow and fast microsecond (μs) time scale dynamics. We further examine the influence of environmental factors such as pH and ATP on the conformational plasticity and the aggregation behavior of FUS-RRM. Our findings show that both ATP and pH perturb the fast and slow μs time scale dynamics of FUS-RRM and thus the aggregation behavior. Specifically, a contrasting effect of ATP on slow and fast μs-ms dynamics at pH 6.4 and 4.6, along with the corresponding changes in aggregation behavior, suggests a complex relationship among ATP, pH, and protein aggregation kinetics. The study suggests that these environmental perturbations behave as kinetic regulators of FUS-RRM's propensity for aggregation.

DOI: https://doi.org/10.1021/jacs.5c15374
bioRxiv. 2025 Dec 25. pii: 2025.12.23.696224. [Epub ahead of print]

Residue-Specific Modulation of Aggregation-Associated Interactions by Spermine in Tau, α-Synuclein, and Aβ40.

Debasis Saha, Sun Xun, Jinghui Luo, Wenwei Zheng.

Preventing neurodegenerative diseases associated with intrinsically disordered proteins (IDPs) remains a major challenge due to the lack of a detailed, sequence-level picture of disease-relevant structures formation and the influence of cellular factors that modulate these transitions. Here, we probe spermine (Spm), a +4 charged polyamine abundant in cells, to determine how it reshapes the conformational ensembles and fibril-associated contact propensities of three disease-linked IDPs: the K18 domain of Tau, α-synuclein (αS) and amyloid-β40 (Aβ40). Using long all-atom molecular dynamics simulations across a range of Spm concentrations, we quantify residue-level changes in intra-chain contacts relative to native contacts observed in fibrils, and corroborate computational predictions with ThT fluorescence assays for Tau constructs. Spm acts in a sequence-and region-specific manner, not simply through overall net charge. In K18, Spm binds near the fourth microtubule binding repeat, disrupting intra-chain contacts associated with Alzheimer's fibril structures and thereby inhibiting aggregation. In αS, Spm binds mainly to acidic residues in the C-terminal half of the sequence and redistributes intramolecular contacts in a way that increases contact propensity in the central aggregation-prone region and therefore aggregation, in line with previous studies showing Spm-enhanced αS aggregation. For Aβ40, Spm neutralizes acidic residues near positions 22-24 and shifts the balance of intra-chain interactions toward its aggregation-prone core, resulting in a net promotion of fibril-like conformations. These divergent effects show that net charge alone cannot predict polyamine influence on IDPs. Instead, residue-specific binding hotspots and local reweighting of aggregation-linked contacts determine whether Spm promotes or suppresses fibril-like conformations. This combined simulation-experimental framework provides a mechanistic basis for how small molecules reprogram IDP conformational ensembles and suggests principles for designing ligands that exploit similar residue-level modulation.

DOI: https://doi.org/10.64898/2025.12.23.696224
J Integr Med. 2025 Dec 16. pii: S2095-4964(25)00191-8. [Epub ahead of print]

Neuroprotective activity of mung bean (Vigna radiata) coat extract via AMPK-dependent autophagy in Alzheimer's and Parkinson's models.

Zhi-Xiong Chen, Fang-Ping Wang, Ya-Ping Li, Meng-Ting Wu, Meng-Yi Chen, Fei-Hong Huang, Yong-Ping Wen, Xin-Hui Wang, Lu Yu, Jian-Ming Wu, An-Guo Wu, Xiao-Gang Zhou.

   OBJECTIVE: Alzheimer's disease (AD) and Parkinson's disease (PD) are major age-related neurodegenerative disorders that currently lack effective disease-modifying therapies. This study investigated the neuroprotective potential and underlying mechanisms of natural products derived from medicine-food homology (MFH) plants, with a focus on autophagy modulation in AD and PD models.
METHODS: Twenty MFH plant extracts were screened using the Caenorhabditis elegans amyloid-β peptide (Aβ) proteotoxicity model CL4176. Mung bean coat extract (MBCE) was identified as a promising candidate and subsequently evaluated in transgenic C. elegans models of AD and PD to assess its effects on pathological protein aggregation, oxidative stress, and behavioral impairments. Autophagy activation was assessed using fluorescence microscopy and lysosomal activity assays. MBCE's effects on protein aggregation and apoptosis were further validated in rat pheochromocytoma (PC-12) cells. Mechanistic insights were obtained through pharmacological inhibition of autophagy and AMP-activated protein kinase (AMPK) signaling, as well as AMPK knockdown. A bioactivity-guided analysis was performed to identify the major active constituents of MBCE.
RESULTS: MBCE significantly alleviated Aβ- and microtubule-associated protein tau (Tau)-induced neurotoxicity in C. elegans by reducing protein aggregation, oxidative stress, and locomotor deficits. It also suppressed α-synuclein accumulation and preserved dopaminergic neuron integrity in PD models. MBCE enhanced stress resistance and activated autophagy, as evidenced by increased autophagosome formation, decreased sequestosome-1 (p62/SQSTM1) levels, and elevated lysosomal activity. RNA interference knockdown assays confirmed that MBCE's neuroprotective effects were dependent on autophagy activation. In PC-12 cells, MBCE similarly induced AMPK-mediated autophagy, reduced the accumulation of disease-related proteins, and mitigated cytotoxicity. Notably, genetic knockdown or pharmacological inhibition of AMPK or autophagy abolished these effects. Vitexin and isovitexin, the main constituents of MBCE, were identified as key contributors to its autophagy-inducing and neuroprotective activities.
CONCLUSION: MBCE mitigates neurodegenerative pathology in AD and PD models by promoting AMPK-dependent autophagy and reducing toxic protein aggregation. These findings support the potential of MBCE as a functional food-based therapeutic strategy for neurodegenerative diseases. Please cite this article as: Chen ZX, Wang FP, Li YP, Wu MT, Chen MY, Huang FH, Wen YP, Wang XH, Yu L, Wu JM, Wu AG, Zhou XG. Neuroprotective activity of mung bean (Vigna radiata) coat extract via AMPK-dependent autophagy in Alzheimer's and Parkinson's models. J Integr Med. 2025; Epub ahead of print.

Keywords:  Alzheimer’s disease; Autophagy; Caenorhabditis elegans; Mung bean coat extract; Parkinson’s disease

DOI:  https://doi.org/10.1016/j.joim.2025.12.003
Proc Natl Acad Sci U S A. 2026 Jan 13. 123(2): e2527258122

Prevention of ubiquitination at K6 and K9 in mutant huntingtin exacerbates disease pathology in a knock-in mouse model.

Pengfei Qi, Libo Yu-Taeger, Hezhou Han, Junbo Zhou, Elisabeth Singer-Mikosch, Nicolas Casadei, Olaf Riess, Noam E Ziv, Aaron Ciechanover, Hoa Huu Phuc Nguyen.

  Huntington disease (HD) is caused by an expansion of the polyglutamine (polyQ) tract in the huntingtin protein (HTT), leading to its misfolding and aggregation. The subcellular localization of mutant HTT (mHTT) aggregates critically influences their neuronal toxicity, with nuclear aggregates contributing more significantly to neurodegeneration than those in the neuropil. Our previous findings demonstrated that site-specific ubiquitination of lysine residues at the positions of K6 and K9 in HTT significantly affect the aggregation properties of mHTT and influence cell viability. However, the in vivo functional relevance of this modification remains elusive. To address this, we generated two HD knock-in (KI) mouse models in which the mouse Htt exon 1 was replaced by human mutant HTT exon 1 containing 134 pure cytosine-adenine-guanine (CAG) repeats. In addition, one of these KI lines carries lysine-to-arginine (K > R) substitutions at residues 6 and 9 to block site-specific ubiquitination (Q134RR line). Compared to Q134KK control mice, Q134RR mice showed a more pronounced accumulation of both soluble and aggregated forms of mHTT. Notably, the K > R substitutions accelerated mHTT aggregation kinetics, resulting in the formation of large inclusion bodies and their exclusive nuclear localization. Furthermore, Q134RR mice exhibited earlier onset and accelerated progression of motor impairments, brain atrophy, and neuropathological features. Collectively, our findings provide strong in vivo evidence for the crucial role of site-specific ubiquitination at K6 and K9 in modulating mHTT aggregation and HD pathology. These results reinforce the therapeutic potential of targeting these specific ubiquitination sites for clinical translation.

Keywords:  aggregation; knock-in mouse model; mutant huntingtin; site-specific ubiquitination

DOI:  https://doi.org/10.1073/pnas.2527258122
Gene. 2026 Jan 05. pii: S0378-1119(26)00009-0. [Epub ahead of print] 150000

cGAS-STING activation in Parkinson's Disease: From mechanisms to Disease-Modifying therapeutic strategies.

Jemimol Solomon, Snehashis Mandal, Khadga Raj Aran.

  Parkinson's disease (PD) is a progressive degenerative neuronal disorder that involves the selective loss of dopaminergic neurons in the substantia nigra, resulting in severe motor and non-motor impairments. Key pathological hallmarks include the accumulation of misfolded α-synuclein and mitochondrial dysfunction. Emerging evidence indicates that innate immune signalling, particularly the cGAS-STING pathway, contributes to PD pathogenesis. It acts as a cytosolic DNA sensor; cGAS can recognise genomic instability or mitochondrial damage by generating an IFN-I response through STING activation. Persistent stimulation of the cGAS-STING pathway in microglia promotes chronic neuroinflammation and contributes to dopaminergic neuronal loss. Mitochondrial dysfunction, impaired DNA repair, and α-Synuclein aggregation may converge to sustain pathway activation, establishing a self-reinforcing cycle of inflammation and neurodegeneration. Understanding the interaction of cGAS-STING signalling, mitochondrial integrity, and protein aggregation offers important mechanistic insights into PD pathology. It suggests meaningful targets for disease-modifying therapeutic approaches for PD that address neuroinflammation and neuronal survival.

Keywords:  Dopaminergic neurons; Parkinson’s disease; Therapeutic targets; Type I interferon; cGAS-STING

DOI:  https://doi.org/10.1016/j.gene.2026.150000
J Cell Biol. 2026 Feb 02. pii: e202212064. [Epub ahead of print]225(2):

Rsp5/NEDD4 and ESCRT regulate TDP-43 toxicity and turnover via an endolysosomal clearance mechanism.

Aaron Byrd, Lucas J Marmorale, Sophia Marcinowski, Megan M Dykstra, Vanessa Addison, Sami J Barmada, J Ross Buchan.

A pathological hallmark in >97% of amyotrophic lateral sclerosis (ALS) cases is the cytoplasmic mislocalization and aggregation of TDP-43, a nuclear RNA-binding protein, in motor neurons. Driving clearance of cytoplasmic TDP-43 reduces toxicity in ALS models, though how TDP-43 clearance is regulated remains controversial. We conducted an unbiased yeast screen using high-throughput dot blotting to identify genes that affect TDP-43 levels. We identified ESCRT complex genes, which induce membrane invagination (particularly at multivesicular bodies; MVBs) and genes linked to K63 ubiquitination (particularly cofactors of the E3 ubiquitin ligase Rsp5; NEDD4 in humans), as drivers of TDP-43 endolysosomal clearance. TDP-43 colocalized and bound Rsp5/NEDD4 and ESCRT proteins, and perturbations to either increased TDP-43 aggregation, stability, and toxicity. NEDD4 also ubiquitinates TDP-43. Lastly, TDP-43 accumulation induces giant MVB-like vesicles, within which TDP-43 accumulates in a NEDD4-dependent manner. Our studies shed light on endolysosomal-mediated cytoplasmic protein clearance, a poorly understood proteostasis mechanism, which may help identify novel ALS therapeutic strategies.

DOI: https://doi.org/10.1083/jcb.202212064
Front Endocrinol (Lausanne). 2025 ;16 1729488

Therapeutic targets in diabetic peripheral neuropathy: heat shock proteins.

Chengzhi Yin, Jiao Lv, Shujia Huang, Chenyu Lang, Yunyun Zhao, Guoqiang Wang, Junming Kan, Xiuge Wang.

  Diabetic peripheral neuropathy (DPN), a debilitating diabetic complication, has a complex pathological mechanism involving oxidative stress, mitochondrial dysfunction, and endoplasmic reticulum stress, and there are no effective disease-mitigating treatments. Current management is restricted to glycaemic control and symptomatic analgesia, both of which offer only modest benefit and carry appreciable adverse-effect profiles. Heat Shock Proteins (HSP) are stress-inducible chaperones that counteract protein misfolding and aggregation. Through suppression of apoptosis, cytoskeletal stabilisation and immune modulation they exert neuroprotective effects relevant to DPN onset and progression. Studies have shown that HSP90 regulates neuronal plasticity and that its inhibitors restore mitochondrial function in diabetic neurons, whereas HSP70 and HSP27 exert context-dependent positive or negative regulation. Subsequent work has evaluated covalent HSP90 inhibitors, novel HSP70 agonists, Trans-activator of transduction-Heat shock protein 27 (TAT-HSP27) mediates suppression of mitochondrial apoptosis and the utility of HSP27 as a circulating biomarker. Here we synthesise recent advances in HSPs biology and DPN pathogenesis, highlight the therapeutic potential of targeting HSPs and outline translational strategies that may expedite disease-modifying therapy.

Keywords:  diabetic peripheral neuropathy; heat shock protein; molecular chaperone; nerve; protein folding

DOI:  https://doi.org/10.3389/fendo.2025.1729488
Mol Neurobiol. 2026 Jan 06. 63(1): 343

MicroRNAs and Long Non-Coding RNAs Affect the Mechanisms Involved in Age-Related Neurodegeneration in a Manner Depending on RNA-Binding Proteins.

Mehrdad Hashemi, Pezhman Shafiei Asheghabadi, Mahdi Moassesfar, Saba Mashhadikhan, Sevda Nasirzade, Ali Vasheghani Farahani, Shaghayegh Mehdizadeh, Shinoo Minaei, Maryam Rahmani, Faranak Jamshidian, Najma Farahani, Russel J Reiter, Afshin Taheriazam, Farzaneh Hasani Sadi, Kiavash Hushmandi, Mina Alimohammadi, Payman Rahimzadeh, Maliheh Entezari.

  Neurodegenerative diseases (NDs), including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD), are marked by progressive neuronal loss and aberrant protein aggregation, presenting substantial global healthcare challenges. Recent research has illuminated the pivotal roles of RNA-binding proteins (RBPs) and non-coding RNAs (ncRNAs), notably microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), in the molecular pathogenesis of age-related neurodegeneration. RBPs orchestrate RNA metabolism and engage extensively with miRNAs and lncRNAs to modulate gene expression at the post-transcriptional level. Dysregulation of these interactions precipitates pathological phenomena such as protein misfolding, stress granule formation, and disrupted RNA processing, thereby exacerbating neuronal dysfunction and death. Specific miRNAs have been implicated in regulating key neurodegenerative biomarkers, including tau and amyloid-β in AD, motor neuron maintenance in ALS, and survival pathways in HD. Elucidating the intricate interplay between RBPs and ncRNAs holds significant promise for the development of therapeutic strategies aimed at ameliorating RNA-mediated mechanisms in neurodegenerative disorders.

Keywords:  Age-related neurodegeneration; Long non-coding RNAs; MicroRNAs; Neurodegenerative diseases; RNA-binding proteins

DOI:  https://doi.org/10.1007/s12035-025-05510-3