bims-proned 2025-10-12 papers

bims-proned

Biomed News

on Proteostasis in neurodegeneration

Issue of 2025–10–12
thirteen papers selected by
Verena Kohler, Umeå University

A novel lncRNA FAM151B-DT regulates degradation of aggregation prone proteins.
Structural polymorphism of α-synuclein fibrils alters the pathway of Hsc70-mediated disaggregation.
Rising Stars: Molecular Mechanisms and Chemical Interventions of α-Synuclein Amyloid Aggregation in Parkinson's Disease.
Hyperactive 20S proteasome enhances proteostasis and ERAD in C. elegans via degradation of intrinsically disordered proteins.
Amyloid-β, Tau, and α-Synuclein Protein Interactomes as Therapeutic Targets in Neurodegenerative Diseases.
Understanding Structural Destabilization and Amyloid Aggregation in ALS-Related Neurodegenerative Disorder: An In Silico and Experimental Analysis of SOD1 Variants.
TDP-43 in Alzheimer's disease: Pathophysiology and therapeutic strategies.
Gut microbiota reconstitution and control of α-synucleinopathy with β-glucans: a promising approach for individuals with parkinson's disease.
Hexagonal Boron Nitride Nanoparticles for Inhibition of Small Fragment Tau Aggregation.
A next-generation HDAC6 inhibitor for amyotrophic lateral sclerosis and frontotemporal dementia.
Incubation with tau aggregates increases hippocampal circuit excitability and enhances long-term depression in acute mouse hippocampal slices.
Spatiotemporal crosstalk among mitochondrial dynamics, NLRP3 inflammasome activation, and histone lactylation drives α-synuclein pathology in prodromal Parkinson's disease.
Discovery of a tau-aggregate clearing compound that covalently targets P4HB.

Mol Psychiatry. 2025 Oct 06.

A novel lncRNA FAM151B-DT regulates degradation of aggregation prone proteins.

Arun Renganathan, Miguel A Minaya, Matthew Broder, Isabel Alfradique-Dunham, Rebecca L Miller, Dhruva D Dhavale, Michelle Moritz, Reshma Bhagat, Jacob Marsh, Anthony Verbeck, Grant Galasso, Emma Starr, David A Agard, Paul T Kotzbauer, Carlos Cruchaga, Celeste M Karch.

Neurodegenerative diseases share common features of protein aggregation along with other pleiotropic traits, including shifts in transcriptional patterns, neuroinflammation, disruption in synaptic signaling, mitochondrial dysfunction, oxidative stress, and impaired clearance mechanisms like autophagy. However, key regulators of these pleiotropic traits have yet to be identified. Here, we used transcriptomics, mass spectrometry, and biochemical assays to define the role of a novel lncRNA on tau pathophysiology. We discovered a long non-coding RNA (lncRNA), FAM151B-DT, that is reduced in a stem cell model of frontotemporal lobar dementia with tau inclusions (FTLD-tau) and in brains from FTLD-tau, progressive supranuclear palsy, Alzheimer's disease, and Parkinson's disease patients. We show that silencing FAM151B-DT in vitro is sufficient to enhance tau and α-synuclein aggregation. To begin to understand the mechanism by which FAM151B-DT mediates tau aggregation and contributes to several neurodegenerative diseases, we deeply characterized this novel lncRNA and found that FAM151B-DT resides in the cytoplasm where it interacts with tau, α-synuclein, HSC70, and other proteins involved in protein homeostasis. When silenced, FAM151B-DT blocks autophagy, leading to the accumulation of tau and α-synuclein. Importantly, we discovered that increasing FAM151B-DT expression is sufficient to promote autophagic clearance of phosphorylated tau and α-synuclein, and reduce tau and α-synuclein aggregation. Overall, these findings pave the way for further exploration of FAM151B-DT as a promising molecular target for several neurodegenerative diseases.

DOI: https://doi.org/10.1038/s41380-025-03277-6
EMBO J. 2025 Oct 06.

Structural polymorphism of α-synuclein fibrils alters the pathway of Hsc70-mediated disaggregation.

Svenja Jäger, Jessica Tittelmeier, Thi Lieu Dang, Tracy Bellande, Virginie Redeker, Alexander K Buell, Janosch Hennig, Ronald Melki, Carmen Nussbaum-Krammer, Bernd Bukau, Anne S Wentink.

  Pathological aggregation of α-synuclein into amyloid fibrils is a hallmark of synucleinopathies, including Parkinson's disease. Despite this commonality, synucleinopathies display divergent disease phenotypes that have been attributed to disease-specific three-dimensional structures of α-synuclein fibrils, each with unique toxic gain-of-function profiles. The Hsc70 chaperone is remarkable in its ability to disassemble pre-existing amyloid fibrils of different proteins in an ATP and co-chaperone-dependent manner. We find, however, using six well-defined conformational polymorphs of α-synuclein fibrils, that the activity of the Hsc70 disaggregase machinery is sensitive to differences in the amyloid conformation, confirming that fibril polymorphism directly affects interactions with the proteostasis network. Amyloid conformation influences not only how efficiently fibrils are cleared by the Hsc70 machinery but also the balance between depolymerization and fragmentation during disaggregation. We further show that, in vitro, the active processing of fibrils by the Hsc70 machinery inadvertently produces seeding competent species that further promote protein aggregation. Amyloid conformation thus is an important feature that can tilt the balance between beneficial or detrimental protein quality control activities in a disease-context.

Keywords:  Alpha-synuclein; Disaggregation; Hsp70; Molecular chaperones; Polymorphism

DOI:  https://doi.org/10.1038/s44318-025-00573-3
J Mol Biol. 2025 Oct 07. pii: S0022-2836(25)00541-8. [Epub ahead of print] 169475

Rising Stars: Molecular Mechanisms and Chemical Interventions of α-Synuclein Amyloid Aggregation in Parkinson's Disease.

Shengnan Zhang, Kaien Liu, Dan Li, Cong Liu.

  Parkinson's disease (PD) is a prevalent neurodegenerative disorder characterized by progressive neuronal loss and pathological aggregation of α-synuclein (α-syn) into amyloid fibrils, which propagate between cells and drive disease progression. Over the past decade, our laboratory has implemented an integrated strategy-combining high-resolution structural biology, molecular biophysics, biochemical and cellular analyses, chemical biology approaches, and in vivo disease models-to elucidate the molecular basis of α-syn pathology. We first determined atomic-resolution structures of full-length α-syn fibrils, revealing diverse polymorphs shaped by familial mutations and post-translational modifications, and linking conformational heterogeneity to phenotypic and pathological diversity. We further elucidated the structural basis underlying the interaction between amyloid fibril and chemical ligands, enabling the rational development of imaging probes and therapeutic modulators. In parallel, we found that the conserved acidic C-terminal region of α-syn fibrils acts as a central interface for driving pathogenic engagement with multiple receptors for neural propagation and inflammation induction, while also binding the autophagy adaptor LC3B to disrupt p62-mediated selective autophagy. Targeting this interface with small molecule inhibitors alleviates α-syn-induced toxicity in cellular models. Together, these findings provide an integrated molecular roadmap for understanding α-syn pathology and advancing precision diagnostics and targeted interventions in PD and related synucleinopathies.

Keywords:  Parkinson’s disease; amyloid fibril; amyloid fibril-ligand interactions; amyloid fibril-receptors interactions; fibril polymorphism; therapeutic intervention; α-synuclein

DOI:  https://doi.org/10.1016/j.jmb.2025.169475
Sci Adv. 2025 Oct 10. 11(41): eadx3014

Hyperactive 20S proteasome enhances proteostasis and ERAD in C. elegans via degradation of intrinsically disordered proteins.

David Salcedo-Tacuma, Nadeem Asad, Md Qamrul Islam, Raymond Anderson, David M Smith.

Age-related proteinopathies, including Alzheimer's and Parkinson's disease, are driven by toxic accumulation of misfolded and intrinsically disordered proteins (IDPs) that overwhelm cellular proteostasis. The proteasome clears these proteins, but its failure in disease remains unclear. We engineered a Caenorhabditis elegans model with a hyperactive 20S proteasome (α3ΔN) for selective 20S activation. α3ΔN markedly enhanced IDP and misfolded protein degradation, reduced oxidative damage, and improved endoplasmic reticulum-associated degradation (ERAD). Aggregation-prone substrates such as vitellogenins and human alpha-1 antitrypsin (ATZ) were efficiently cleared. Integrated proteomic and transcriptomic analyses reveal systemic adaptations featuring increased protein turnover and oxidative stress resistance independent of superoxide dismutases (SODs). Notably, α3ΔN extended life span and stress resistance independently of canonical unfolded protein response (UPR) signaling via xbp-1. These findings substantiate a "20S pathway" of proteostasis that directly alleviates protein aggregation and oxidative stress, offering a promising therapeutic angle for neurodegenerative diseases.

DOI: https://doi.org/10.1126/sciadv.adx3014
Cell Mol Neurobiol. 2025 Oct 06. 45(1): 84

Amyloid-β, Tau, and α-Synuclein Protein Interactomes as Therapeutic Targets in Neurodegenerative Diseases.

D Mohan Kumar, Priti Talwar.

  Alzheimer's and Parkinson's disease are the most prevalent neurological diseases. Amyloid-β, tau, and α-synuclein proteins are known to be implicated in neurodegenerative disease (NDD). Elucidation of precise therapeutic targets remains a challenge. Therefore, the identification of interactomes of amyloid-β precursor protein (APP), microtubule-associated protein tau (MAPT), and α-synuclein (SNCA) proteins is of great interest, aimed at unraveling novel targets. An integrated analysis was employed to identify direct interactors as therapeutic targets, considering protein-protein interactions and subsequent network analysis. Further, it was proposed to identify hub proteins, intended targets, regulatory factors, disease-gene associations, functional enrichment analyses of the protein interactors interfered with gene ontologies and disease-driving pathways. Protein interactome centered on APP, MAPT, and SNCA identified the top hundred high-confidence protein-protein interactions that revealed BACE1, PSEN1, SORL1, GSK3B, CDK5, SNCAIP, PRKN, and APOE as physical and functional protein interactors. The top ten hub proteins were ranked based on multiple centrality measures and topological algorithms. Further, the integrated network of all three protein interactomes contained distinct nodes with edges. Interestingly, regulatory mechanisms have revealed possible regulatory modules, including cleavage, phosphorylation, and ubiquitination. Top interacting proteins were enriched in several ontology terms, such as regulation of neuronal apoptotic processes, amyloid beta fibril formation, and tau protein binding. Pathway analysis mapped the pathways of neurodegeneration-multiple disease, with a significant level of interacting proteins. Finally, the most comprehensive interactome associated with NDD provides insights into protein interactors, regulating the mechanisms of key proteins that can serve as novel therapeutic targets.

Keywords:  Amyloid-β; Protein interactomes; Tau protein; Therapeutic targets; α-synuclein

DOI:  https://doi.org/10.1007/s10571-025-01604-7
ACS Chem Neurosci. 2025 Oct 09.

Understanding Structural Destabilization and Amyloid Aggregation in ALS-Related Neurodegenerative Disorder: An In Silico and Experimental Analysis of SOD1 Variants.

Nazanin Soleimanifard, Bagher Seyedalipour, Payam Baziyar, Saman Hosseinkhani.

  Protein misfolding has been reported as a common symptom in many neurodegenerative diseases, leading to the formation of protein aggregates. Metal ions (holo form) are critical for the folding and function of WT-SOD1, whereas their absence (apo form) can lead to aggregation and misfolding under physiological conditions. Therefore, this study investigates the role of mutations/metal deficiencies in the metal binding loop and how the mutations affect the SOD1 aggregation process in amyotrophic lateral sclerosis through an experimental and computational approach. Molecular dynamic (MD) simulation results show a significant difference in apo-SOD1 compared to holo-SOD, which is consistent with experimental studies. Dictionary of Secondary Structure in Proteins (DSSP), Fourier-transform infrared (FTIR), and Circular dichroism (CD) results confirmed a tendency for increased β-sheet formation in the apo-SOD1 form, which can be attributed to protein aggregation. The observed conformational changes under amyloidogenic conditions suggest that the hydrophobic pockets in apo-SOD1 are more exposed compared to holo-SOD1, as confirmed by ANS fluorescence. Thermodynamic investigations with GdnHCl demonstrated that mutation/metal deficiency are necessary to trigger the misfolding and aggregation of SOD1. Our results show that apo/holo SOD1 variants induce the formation of aggregated species under physiological conditions. These aggregates are detected by Congo red and ThT fluorescence and further validated by transmission electron microscopy (TEM) imaging. Overall, mutations in loop IV and structural abnormalities such as mutation/metal deficiency and reduced disulfide bonds synergistically lead to reduced thermodynamic stability of SOD1 variants, facilitating the formation of amyloid/amorphous aggregates. Ultimately, this study could serve as a basis for new research to develop new treatments for neurological disorders, and help to better understand the role of mutation in the formation of amyloid aggregates and identify different factors in ALS disease.

Keywords:  MD simulation; N65S mutant; SOD1; amyloid; amyotrophic lateral sclerosis; protein aggregation

DOI:  https://doi.org/10.1021/acschemneuro.5c00350
Pharmacol Res. 2025 Oct 04. pii: S1043-6618(25)00402-5. [Epub ahead of print]221 107977

TDP-43 in Alzheimer's disease: Pathophysiology and therapeutic strategies.

Xinyu Zhou, Xianmei Lin, Yuqi He, Nanqu Huang, Yong Luo.

  Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by the dysregulation of multiple molecular mechanisms. In recent years, transactive response DNA-binding protein 43 kDa (TDP-43) has increasingly been recognized as a critical pathological protein and has become a prominent focus in AD research. TDP-43 is involved not only in physiological processes such as RNA metabolism, protein quality control, and mitochondrial regulation but also in AD pathology through abnormal aggregation, dysregulated nucleocytoplasmic transport, and aberrant posttranslational modifications, leading to neurotoxicity, mitochondrial dysfunction, and disrupted protein homeostasis. Studies have shown that TDP-43 closely interacts with two core pathological hallmarks of AD, β-amyloid (Aβ) and tau. By promoting Aβ oligomerization and tau hyperphosphorylation, TDP-43 accelerates the pathological progression of this disease. Given the multifaceted role of TDP-43 in AD, therapeutic strategies targeting TDP-43 have shown great potential. Approaches such as modulating its RNA splicing activity, inhibiting pathological aggregation, restoring the balance of nucleocytoplasmic transport, and preventing its mitochondrial localization offer new avenues for AD treatment. This review systematically summarizes the pathological mechanisms of TDP-43 in AD and its interactions with Aβ and tau and discusses the feasibility of targeting TDP-43 as a therapeutic strategy. Future studies should further elucidate the role of TDP-43 in the early stages of AD and develop specific therapeutic agents that target TDP-43, with the aim of providing new insights for precision treatment of AD.

Keywords:  Alzheimer's disease; Mitochondrial dysfunction; Tau; Transactive response DNA-binding protein 43kDa; β-amyloid

DOI:  https://doi.org/10.1016/j.phrs.2025.107977
Metab Brain Dis. 2025 Oct 11. 40(7): 287

Gut microbiota reconstitution and control of α-synucleinopathy with β-glucans: a promising approach for individuals with parkinson's disease.

Faezeh Hatami, Zahra Aghelan, Mahan Rezaie Pouya, Melina Moulaeian, Ali Rastegari, Seyed Hosien Abtahi, Shaghayegh Hoseini.

  Parkinson's disease (PD) ranks as the second most prevalent neurodegenerative condition affecting individuals in their middle age and beyond. Its hallmark features include the abnormal accumulation of α-synuclein protein and the progressive loss of dopaminergic neurons. A substantial body of evidence supports the notion that an imbalance in the gut microbiome, known as dysbiosis, contributes to the misfolding and accumulation of α-synuclein, a key pathological feature of PD. This finding raises the possibility that restoring the gut microbiome, particularly the bacteria associated with α-synuclein, could serve as a promising therapeutic approach for PD. There is evidence that β-glucan can play an important role in the reconstitution of gut microbiome. In this regard, this study reviews the evidence showing the role of β-glucan in reducing α-synuclein accumulation and mitigating the progression of PD. This scooping review study presents promising prospects for advancing novel therapeutic approaches to benefit individuals with PD.

Keywords:  Gut microbiota; Parkinson's disease; Α-synuclein; Β- glucan

DOI:  https://doi.org/10.1007/s11011-025-01711-w
J Phys Chem B. 2025 Oct 06.

Hexagonal Boron Nitride Nanoparticles for Inhibition of Small Fragment Tau Aggregation.

Srijita Paul, Lalitha Guruprasad.

The aberrant folding of the Tau protein is correlated with several neurodegenerative diseases, such as Alzheimer's and other tauopathies. Recent studies on the neurotoxic species of Tau have identified some smaller nucleating domains of the full-length protein to initiate Tau aggregation and are shown as potential therapeutic targets in Tau pathology. Two hexapeptides, namely, PHF6 (306VQIVYK311) and PHF6* (275VQIINK280), have been recognized as the most important aggregation-prone Tau fragments among all. Currently, low-dimensional nanomaterials have shown a plethora of applications in bionanomedicine, including the treatment of amyloid diseases. Hexagonal boron nitride (h-BN) nanoparticles, analogous to carbon nanomaterials, have become potential candidates in this field due to their lower cytotoxicity compared to carbon nanoparticles and biocompatibility. In this study, we have explored the aggregation pattern of PHF6 and PHF6* and the effects of a two-dimensional (2D) h-BN nanosheet (BNNS) on these peptide oligomerizations. Atomistic simulations reveal that the PHF6-PHF6 homomer aggregation is highly favored due to the aromatic π-π interaction between the Tyr residues; furthermore, the heteromeric interaction between PHF6 and PHF6* is stronger than the self-association of PHF6* homomers. In the presence of BNNS, the peptides get absorbed on the nanosurface through weak hydrophobic interactions and aromatic π-π stacking and remain in their monomeric random coil structure. Also, the h-BN nanosheet can destabilize the preformed oligomers of the hexapeptides, hence providing a new direction toward the use of h-BN and other related nanomaterials as potential antiaggregating agents against amyloid deposition.

DOI: https://doi.org/10.1021/acs.jpcb.5c04935
Brain. 2025 Oct 08. pii: awaf380. [Epub ahead of print]

A next-generation HDAC6 inhibitor for amyotrophic lateral sclerosis and frontotemporal dementia.

Rebecca E James, Michael Bekier, Pin-Tsun Justin Lee, Frederick A Schroeder, Lauren T Evans, Florence F Wagner, Dean Hickman, Tom Richardson, Theo Hatzipetros, Fernando Vieira, Noëlle Callizot, Souvik Modi, Jacob M Hooker, Janice E Kranz, Robert H Brown, Sami J Barmada, Tonya M Gilbert.

  Dysregulated proteostasis and intracellular transport contribute to neurodegeneration. HDAC6, a therapeutic target of interest for neurodegenerative diseases, acts at a nexus modulating both proteostasis and intracellular transport. Inhibition of HDAC6 deacetylase activity promotes autophagic clearance of protein aggregates and increases ⍺-tubulin acetylation, thereby enhancing microtubule resiliency and motor protein-microtubule binding, which facilitates intracellular transport and, subsequently, proteostasis. Despite these benefits, advancement of HDAC6 inhibitor therapeutics for neurodegenerative disease has been hindered by inadequate selectivity and CNS-penetrance of first-generation compounds. Here we characterize a next-generation small molecule HDAC6 inhibitor, EKZ-438, in preclinical models of amyotrophic lateral sclerosis and frontotemporal dementia. We present the pharmacological properties of EKZ-438, which demonstrate high selectivity for HDAC6 (>8,500-fold selectivity for HDAC6 versus all other HDAC6 paralogs), low nanomolar potency (12 nM) for HDAC6, and, importantly, CNS-penetrance (Kp,uu,brain) ≥ 0.55 and high oral bioavailability (F% = 70). In complementary preclinical in vitro and in vivo immunolabeling and live imaging studies we tested the hypothesis that selective inhibition of HDAC6 deacetylase activity is sufficient to improve pathophysiological proteostasis and intracellular transport deficits in animal models of familial and sporadic amyotrophic lateral sclerosis and frontotemporal dementia. Notably, we extended these findings to human induced pluripotent stem cell-derived neuronal cellular models, supporting the relevance of our findings to human disease. EKZ-438 treatment fully rescued SOD1 (q < 0.0001) and TDP-43 (q < 0.001) proteostasis defects following an excitotoxic glutamate challenge, and increased survival of SOD1G93A and wildtype motor neurons by 59% (q < 0.0001) and 37% (q < 0.01), respectively, demonstrating in vitro neuroprotection. In SOD1G93A mice, EKZ-438 improved axonal transport by 16% (q < 0.05), motor performance by ∼40% (q < 0.05), and decreased plasma neurofilament light chain levels by 35% (q < 0.05), demonstrating in vivo neuroprotection. In a TDP-43 mouse model, EKZ-438 reduced TDP-43 pathology by ∼30% (q < 0.05) and neuroinflammation by ∼26% (q < 0.05) in the brain, supporting HDAC6 inhibition for sporadic amyotrophic lateral sclerosis and frontotemporal dementia. Furthermore, EKZ-438 treatment improved intracellular transport by 39% (q < 0.001), rescued cytoplasmic TDP-43 accumulation by 87% (q < 0.0001), and restored nuclear TDP-43 splicing activity (P < 0.05) in human TARDBP neurons. These mechanistic improvements aligned with nearly complete rescue of human TARDBP and C9orf72 mutant neuron survival (P < 0.0001). We conclude that selective HDAC6 inhibition represents a promising therapeutic approach for potential disease modification in amyotrophic lateral sclerosis and frontotemporal dementia.

Keywords:  ALS; FTD; HDAC6 inhibitor; axonal transport; proteostasis

DOI:  https://doi.org/10.1093/brain/awaf380
Front Neural Circuits. 2025 ;19 1596989

Incubation with tau aggregates increases hippocampal circuit excitability and enhances long-term depression in acute mouse hippocampal slices.

Alice Wang, Abbie Richardson, Isabelle Emmett, Daniel Friedmann, Saskia Bakker, Magnus Richardson, Emily Hill, Mark Wall.

  Aggregation of the protein tau is a key pathological hallmark of tauopathies such as Alzheimer's Disease. Tau dissociates from microtubules and diffuses from the axon into the soma-dendritic compartment, where it aggregates firstly into oligomers and ultimately into neurofibrillary tangles. There is gathering evidence that it is the soluble tau aggregates that are the major active species and that their effects on neuronal electrophysiological properties, synaptic transmission and plasticity could contribute to early cognitive decline. Here we have investigated the effects of incubating acute mouse hippocampal slices with recombinant tau aggregates. We observed interictal events and an increase in excitability of CA3 pyramidal cells. Tau aggregates had little effect on basal synaptic transmission but antagonism of GABAA receptors revealed significant effects of tau aggregates, enhancing the firing of population spikes and the occurrence of bursts following fEPSPs. Tau aggregates produced a concentration-dependent impairment of long-term potentiation (LTP), which could not be overcome by repeated LTP induction stimuli, demonstrating the effects were not just through an elevation of LTP threshold. In contrast to the impairment of LTP, tau aggregates increased G1-mGluR-dependent LTD. Thus, tau aggregates increase hippocampal circuit excitability and shift synaptic plasticity towards depression.

Keywords:  electrophyisology; long term potentiation (LTP); synaptic plasiticity; tauopathies; whole cell patch clamp

DOI:  https://doi.org/10.3389/fncir.2025.1596989
Front Cell Neurosci. 2025 ;19 1636185

Spatiotemporal crosstalk among mitochondrial dynamics, NLRP3 inflammasome activation, and histone lactylation drives α-synuclein pathology in prodromal Parkinson's disease.

Peizhu Lv, Xia Chen, Shiping Liu, Yu Zhang, Yan Bai, Shun Wang, Yulin Wang.

  This article conducts a systematic search of literature in the fields of neuroscience, cell biology, immunometabolism, etc. from 1990 to 2025, with PubMed/WebofScience as the core database. Experimental and clinical studies covering the core mechanisms of the preprophase of PD (mitochondrial imbalance → NLRP3 activation → lactation modification → α -SYN pathology) were included, and non-interaction mechanisms and clinical-phase studies were excluded. The pathological interaction network of mitochondrial dynamic imbalance, lysosomes - mitochondrial interaction disorder and neuroinflammation in Parkinson's disease (PD) was explained. Construct a three-dimensional pathological network of "energy-inflammation-protein homeostasis" to provide a theoretical basis for early intervention. The imbalance of mitochondrial fission/fusion leads to the accumulation of fragmented mitochondria, triggering energy metabolism disorders and oxidative stress; abnormal aggregation of α-synuclein (α-syn) disrupts mitochondrial-endoplasmic reticulum membrane (MAM) calcium signaling, upregulates Miro protein to inhibit mitochondrial autophagy clearance, forming a vicious cycle of neuronal damage. Defects in the PINK1/Parkin pathway and LRRK2 mutations interfere with the turnover of mitochondrial fission complexes, causing mtDNA leakage, activating the NLRP3 inflammasome, and driving neuroinflammatory cascades. Additionally, lysosomal dysfunction caused by GBA1 mutations exacerbates mitochondrial quality control defects through Rab7 activity imbalance. Abnormal lactate metabolism may influence inflammasome activity through epigenetic regulation, but its role in PD needs further validation. Based on the above mechanisms, a diagnostic strategy for the prodromal phase integrating dynamic monitoring of mitochondrial fragmentation index, lysosomal function markers, and inflammatory factors is proposed, along with new intervention directions targeting Drp1, NLRP3, and the lysosome-mitochondria interface.

Keywords:  NLRP3 inflammasome; Parkinson’s disease; lactylation modification; mitochondrial dynamics; prodromal phase

DOI:  https://doi.org/10.3389/fncel.2025.1636185
Cell Chem Biol. 2025 Oct 06. pii: S2451-9456(25)00301-0. [Epub ahead of print]

Discovery of a tau-aggregate clearing compound that covalently targets P4HB.

Louis P Conway, Michelle A Estrada, Weichao Li, Stephen Walker, Benjamin Mielich-Süss, Anurupa Shrestha, Matthew Townsend, Jürgen Korffmann, Greg Potts, Janice Lee, Kenneth P Robinson, Shiyao Wang, Brian Bierie, John R Koenig, Phil Cox, Paul Richardson, Manisha Jhala, Becca McCloud, Sujatha Gopalakrishnan, Kevin Woller, Anil Vasudevan, Scott E Warder, Shaun M McLoughlin, Christopher G Parker.

  The improper folding and aggregation of tau are linked to several neurodegenerative diseases affecting millions worldwide. However, the pathogenesis of tauopathies remains poorly understood, resulting in limited effective treatments. Here, we employ an integrated chemoproteomic phenotypic strategy to identify druggable targets and corresponding chemical probes for the treatment of tauopathies. We identified and optimized an indole-amine compound that potently and extensively clears tau aggregates in two human tauopathy models. Mechanistic and chemoproteomic studies implicate protein disulfide isomerase 1 (P4HB) as the primary target, forming covalent adducts upon metabolic activation. Knockdown of P4HB reduced tau aggregates in three tauopathy models, including an ex vivo murine neuron preclinical model. Functional characterization revealed the compound induces mild endoplasmic reticulum (ER)-stress responses as assessed by RNA sequencing and whole proteomic profiling. Our findings highlight P4HB as a potential therapeutic target for treatment of tauopathies.

Keywords:  chemoproteomics; neurodegenerative disease; phenotypic screening; target identification; tauopathy

DOI:  https://doi.org/10.1016/j.chembiol.2025.09.006