bims-proned 2025-06-22 papers

bims-proned

Biomed News

on Proteostasis in neurodegeneration

Issue of 2025–06–22
eighteen papers selected by
Verena Kohler, Umeå University

DNAJB6: A guardian against neurodegeneration.
C-Terminal Radical Oxidation Inhibits α-Synuclein Aggregation and Cytotoxicity via an Oxidative Oligomer-Disrupting Pathway.
Amyloid formation of alternatively spliced variants of α-synuclein.
ACLY links mutant α-synuclein to metabolism, autophagy and neurodegeneration.
ATP as a key modulator of fused-in-sarcoma phase separation and aggregation: Insights into amyotrophic lateral sclerosis pathogenesis.
Lysosomal targeting of liposomes with acidic pH and Cathepsin B induces protein aggregate clearance.
Pathological α-synuclein elicits granulovacuolar degeneration independent of tau.
Cryo-EM structural analyses reveal diverse porous structures in brain-derived tau oligomers.
Poly-γ-glutamic acid alleviates cytotoxicity and inflammation induced by pre-formed fibrils of α-synuclein in murine primary astrocytes.
Purification tags markedly affect self-aggregation of CPEB3.
Allium sativum-Derived Alliin and Allicin Stably Bind to α-Synuclein and Prevent Its Cytotoxic Aggregation.
Proteostasis signatures in human diseases.
Aneuploidy-induced proteostasis disruption impairs mitochondrial functions and mediates aggregation of mitochondrial precursor proteins through SQSTM1/p62.
Recent Progress of Small-molecule Inhibitors of O-GlcNAcase for Alzheimer's Disease.
Calcium homeostasis modulator 2 aggravates α-synuclein-induced neurotoxicity in Parkinson's disease by activating PARP-1 depended Parthanatos.
Differential pathological dynamics triggered by distinct Parkinson patient-derived α-synuclein extracts in nonhuman primates.
A mechanistic model of pure and lipidic α-synuclein aggregation for advancing Parkinson's therapies.
A hypothesis explaining Alzheimer's disease, Parkinson's disease, and dementia with Lewy bodies overlap.

Neural Regen Res. 2025 Jun 19.

DNAJB6: A guardian against neurodegeneration.

Jónvá Hentze, Anna Gelman, Tomasz Brudek, Christian Hansen.

   ABSTRACT: Amyloid protein aggregation plays a major role in multiple neurodegenerative diseases and is likely the primary driving force for the progression of most of these diseases. Multiple recent studies have highlighted that the DNAJ homolog subfamily B member 6 (DNAJB6) chaperone is particularly interesting, when it comes to preventing amyloidogenic proteins from aggregating. It has been shown that DNAJB6 can prevent the aggregation of polyglutamine-expanded proteins in models of Huntington's disease. Likewise, it can suppress aggregation of α-synuclein in models of Parkinson's disease and other synucleinopathies. Finally, it has been shown that DNAJB6 can block aggregation of multiple additional amyloid proteins involved in Alzheimer's disease and other tauopathies as well. We believe there is yet much to learn about the protective role of DNAJB6 in the brain, but this focused review summarizes, what we know so far of this chaperone. It describes the biological role of DNAJB6 in the brain and its interaction with Hsp70, with particular emphasis on the studies that show its ability to prevent amyloid protein aggregation in vitro and in vivo. Moreover, recent work on dysregulation of the expression of DNAJB6 in brain clinical tissue is discussed. Finally, we discuss potential therapeutic perspectives as we believe this protein is a promising druggable target.

Keywords:  DNAJB6; aggregation; chaperones; clinical tissues; human brain; neurodegeneration; neurodegenerative diseases; therapeutic target

DOI:  https://doi.org/10.4103/NRR.NRR-D-24-01504
J Am Chem Soc. 2025 Jun 18.

C-Terminal Radical Oxidation Inhibits α-Synuclein Aggregation and Cytotoxicity via an Oxidative Oligomer-Disrupting Pathway.

Xiaoli Wang, Tingting Liang, Anran Jin, Chenao Zhang, Jiaxin Zhou, Mingrui Li, Ziyi Sun, Gongyu Li.

α-Synuclein (α-Syn) aggregation is a hallmark of Parkinson's disease and other neurodegenerative disorders. This study investigates the impact of controlled radical oxidation on α-Syn aggregation and associated cytotoxicity. Using a microscale low-temperature plasma device for submillisecond radical oxidation, combined with native ion mobility-mass spectrometry and liquid chromatography-tandem mass spectrometry, we demonstrate radical-directed preferential oxidation of the α-Syn C-terminal region. This targeted oxidation leads to the inhibition of protein aggregation and reduced cytotoxicity in SH-SY5Y cells. Mechanistic analysis reveals that ultrafast C-terminal radical oxidation impairs α-Syn oligomerization propensity, likely by preventing conformational transitions critical for forming stable amorphous deposits and well-ordered fibers. Notably, this inhibitory effect is specific to monomer oxidation prior to aggregation rather than oxidation of preformed fibers. Our findings unveil a novel oxidative oligomerization-disrupting pathway that modulates α-Syn fibrillization behavior, offering new insights into the complex interplay between oxidative stress and protein aggregation in neurodegenerative diseases. This study challenges conventional views of the detrimental role of oxidative stress in α-Syn pathology and suggests potential neuroprotective strategies based on targeted oxidative modifications.

DOI: https://doi.org/10.1021/jacs.5c06792
Protein Sci. 2025 Jul;34(7): e70195

Amyloid formation of alternatively spliced variants of α-synuclein.

Daniel Q SanGiovanni, Ryan P McGlinchey, Jennifer C Lee.

  Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy are disorders characterized by the presence of cytosolic α-synuclein (SNCA) amyloids. The gene SNCA is alternatively spliced, generating three variants of SNCA, missing exon 3 (SNCAΔ3) or 5 (SNCAΔ5), or both exons (SNCAΔ3Δ5). Despite purported upregulation in disease states, their pathological relevance is ill-defined. Here, we investigated the amyloid formation of alternatively spliced variants under physiological conditions. Aggregation kinetics, secondary structure, and fibril morphology of N-terminally acetylated SNCAΔ3, SNCAΔ5, and SNCAΔ3Δ5 were assessed by thioflavin-T fluorescence, circular dichroism spectroscopy, and transmission electron microscopy, respectively. Compared to SNCA, both SNCAΔ5 and SNCAΔ3Δ5 aggregate faster and adopt a more twisted fibril morphology, whereas SNCAΔ3 is more sensitive to solution conditions, exhibiting similar or modestly faster aggregation kinetics compared to SNCA. Cross-seeding experiments using spliced-variant fibrils and soluble SNCA showed that despite fibril morphological differences, SNCAΔ5 were competent seeds for SNCA, which is explained by their similar protease-K resistant regions. Contrastingly, neither SNCAΔ3 nor SNCAΔ3Δ5 fibrils cross-seed SNCA, indicating exon 3 (residues 41-54) is essential in modulating fibril structure. Notably, SNCA aggregation is stimulated by sub-stoichiometric amounts of soluble SNCAΔ5 and SNCAΔ3Δ5, but not SNCAΔ3, suggesting that exon 5 (residues 103-130) is more important in modulating aggregation kinetics. Taken together, we propose that alternatively spliced variants are pathogenic by exacerbating aggregation of the main SNCA isoform.

Keywords:  Parkinson's disease; aggregation; alternative splicing; amyloid; circular dichroism; electron microscopy; fibril; kinetics; α‐synuclein

DOI:  https://doi.org/10.1002/pro.70195
Neuron. 2025 Jun 18. pii: S0896-6273(25)00425-8. [Epub ahead of print]113(12): 1847-1849

ACLY links mutant α-synuclein to metabolism, autophagy and neurodegeneration.

Frédéric Saudou.

In this issue of Neuron, Son et al.1 reveal how pathologic α-synuclein inhibits autophagy, leading to neurodegeneration. Their work highlights the key roles of the acetyl-CoA-producing enzyme ACLY and aberrant cytoplasmic p300 acetylation, uncovering new therapeutic strategies for Parkinson's disease.

DOI: https://doi.org/10.1016/j.neuron.2025.05.027
J Mol Biol. 2025 Jun 12. pii: S0022-2836(25)00361-4. [Epub ahead of print] 169295

ATP as a key modulator of fused-in-sarcoma phase separation and aggregation: Insights into amyotrophic lateral sclerosis pathogenesis.

Keiji Kitamura, Itta Tsukui, Fuka Sasaki, Yutaro Shiramasa, Miyu Arayama, Manoto Morishita, Ayano Oshima, Soichiro Kitazawa, Tomoshi Kameda, Ryo Kitahara.

  Fused in sarcoma (FUS) is an RNA-binding protein, the aberrant aggregation of which is linked to amyotrophic lateral sclerosis (ALS). Liquid-liquid phase separation (LLPS) of FUS facilitates functional condensate formation and can drive pathological aggregation under certain conditions. The aggregation-inhibitory effects of ATP, a key cellular hydrotrope, have been reported for multiple proteins; however, how ATP, present at approximately 1-12 mM concentrations in cells, regulates LLPS and amyloid fibril formation remains unclear. Therefore, we investigated how ATP modulates the LLPS behavior and aggregation of FUS and its ALS-linked variants, R495X and P525L. ATP destabilized both normal LLPS and aberrant high-pressure LLPS (HP-LLPS), with a relatively strong inhibitory effect on HP-LLPS. Pressure-jump experiments demonstrated that ATP reduced the irreversible aggregation propensity of HP-LLPS, particularly in ALS variants that exhibited enhanced aggregation compared to that by wild-type FUS. Molecular dynamic simulations further revealed that the triphosphate and adenosine moieties of ATP synergistically disrupted intermolecular interactions that were crucial for phase separation, leveraging its amphipathic properties. Notably, ATP concentrations within the physiological range (1-12 mM) significantly inhibited FUS aggregation, suggesting a protective role in cellular environments. These results indicate that decreased intracellular ATP levels may exacerbate aberrant phase transitions of FUS, contributing to ALS onset. This study underscores the potential of ATP as a therapeutic modulator of protein phase separation and aggregation, providing valuable insights into the molecular mechanisms of ALS. Our findings open new avenues for targeting ATP-regulated pathways for treating neurodegenerative disorders.

Keywords:  P525L; R495X; amyotrophic lateral sclerosis; liquid-liquid phase separation; pressure

DOI:  https://doi.org/10.1016/j.jmb.2025.169295
Cell Commun Signal. 2025 Jun 19. 23(1): 296

Lysosomal targeting of liposomes with acidic pH and Cathepsin B induces protein aggregate clearance.

Minsol Jeon, Da-Eun Kim, So Young Choi, Seoyoung Kim, Seongchan Kim, Hyojin Lee, Hyunkyung Kim.

  The autophagy-lysosomal pathway is a cellular degradation mechanism that regulates protein quality by eliminating aggregates and maintaining normal protein function. It has been reported that aging itself reduces lysosomal proteolytic activity in age-related neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease. Reduction in lysosomal function may underlie the accumulation of protein aggregates such as amyloid beta (Aβ), tau, and α-synuclein. Some of these protein aggregates may cause additional lysosomal dysfunction and create a vicious cycle leading to a gradual increase in protein aggregation. In this study, liposome-based lysosomal pH-modulating particles (LPPs), containing a liquid solution to adjust lysosomal pH, have been developed to restore lysosomal function. The results demonstrate that acidic LPPs effectively restore lysosomal function by recovering lysosomal pH and facilitating the removal of protein aggregates. These findings demonstrated that acidic LPPs could effectively recover the abnormal lysosomal function via restoration of lysosomal pH and enhance the clearance of protein aggregates. Furthermore, the simultaneous introduction of Cathepsin B (CTSB) proteins and acidic LPP revealed a synergistic effect, promoting lysosomal pH recovery and enhancing aggregates removal. These findings suggest a novel strategy for improving lysosomal clearance activity in proteinopathies.

Keywords:  Aggregate clearance; Autophagy; Cathepsin; Lysosome; Proteinopathy

DOI:  https://doi.org/10.1186/s12964-025-02310-z
Transl Neurodegener. 2025 Jun 19. 14(1): 31

Pathological α-synuclein elicits granulovacuolar degeneration independent of tau.

Dylan J Dues, Madalynn L Erb, Alysa Kasen, Naman Vatsa, Erin T Williams, An Phu Tran Nguyen, Michael X Henderson, Darren J Moore.

   BACKGROUND: Pathologic heterogeneity is a hallmark of Lewy body dementia (LBD), yet the impact of Lewy pathology on co-pathologies is poorly understood. Lewy pathology, containing α-synuclein, is often associated with regional tau pathology burden in LBD. Similarly, granulovacuolar degeneration bodies (GVBs) have been associated with tau pathology in Alzheimer's disease. Interestingly, GVBs have been detected in a broad range of neurodegenerative conditions including both α-synucleinopathies and tauopathies. Despite the frequent co-occurrence, little is known about the relationship between α-synuclein, tau, and granulovacuolar degeneration.
METHODS: We developed a mouse model of limbic-predominant α-synucleinopathy by stereotactic injection of mouse α-synuclein pre-formed fibrils (PFFs) into the basal forebrain. This model was used to investigate the relationship of α-synuclein pathology with tau and GVB formation.
RESULTS: Our model displayed widespread α-synuclein pathology with a limbic-predominant distribution. Aberrantly phosphorylated tau accumulated in a subset of α-synuclein inclusion-bearing neurons, often colocalized with lysosomes. Many of these same neurons also contained CHMP2b- and CK1δ-positive granules, established markers of GVBs, which suggests a link between tau accumulation and GVB formation. Despite this observation, GVBs were also detected in tau-deficient mice following PFF injection, suggesting that pathological α-synuclein alone is sufficient to elicit GVB formation.
CONCLUSIONS: Our findings support that α-synuclein pathology can independently elicit granulovacuolar degeneration. The frequent co-accumulation of tau and GVBs suggests a parallel mechanism of cellular dysfunction. The ability of α-synuclein pathology to drive GVB formation in the absence of tau highlights the broader relevance of this process to neurodegeneration with relevance to the pathobiology of LBD.

Keywords:  Alpha-synuclein; Animal model; Granulovacuolar degeneration; Lewy pathology; Neurodegeneration; Protein aggregation; Tau

DOI:  https://doi.org/10.1186/s40035-025-00494-5
Biochem Biophys Res Commun. 2025 Jun 09. pii: S0006-291X(25)00904-0. [Epub ahead of print]776 152189

Cryo-EM structural analyses reveal diverse porous structures in brain-derived tau oligomers.

Anvesh K R Dasari, Nemil Bhatt, Md Anzarul Haque, Robert Irving, Rakez Kayed, Kwang Hun Lim.

  Misfolding and aggregation of tau into oligomers and neurofibrillary tangles are associated with Alzheimer's disease and related dementia (ADRD). Misfolded oligomeric species are widely believed to play a critical role in both disrupting cellular functions and propagating protein misfolding between cells. Characterization of the misfolded oligomers is crucial for understanding the mechanisms underlying protein aggregation and its role in disease pathogenesis. However, structural characterization of these misfolded oligomers has proven challenging due to their transient and heterogeneous nature. Here we report structural features of brain-derived tau oligomers extracted from Alzheimer's brains. Initial screening using negative staining transmission electron microscopy (TEM) and atomic force microscopy (AFM) reveal that tau (2N4R) forms a diverse array of pore-like oligomers with a diameter of 5-20 nm and a height of ∼2-8 nm. Higher-resolution structural analyses using cryo-EM on oligomers with diameters of 10-20 nm revealed the presence of two distinct layers within the pore-like structures, resolved at 2.5-4 Å. Our structural studies support the hypothesis that misfolded proteins may function as pore-forming toxins, potentially disrupting cellular membranes.

Keywords:  ADRD; Brain-derived oligomer; Cryo-EM; Misfolding; Pore-like oligomers; Tau

DOI:  https://doi.org/10.1016/j.bbrc.2025.152189
Int J Biol Macromol. 2025 Jun 16. pii: S0141-8130(25)05858-1. [Epub ahead of print]318(Pt 4): 145303

Poly-γ-glutamic acid alleviates cytotoxicity and inflammation induced by pre-formed fibrils of α-synuclein in murine primary astrocytes.

Claudia Novello, Mattia Parati, Samanta Mazzetti, Oriana Rampoldi, Huseyin Berkcan Isilgan, Milo Jarno Basellini, Chiara M G De Luca, Arianna Ciullini, Ilaria L Dellarole, Alessandro Fantin, Isabella Russo, Brian L Johnston, Moira Paroni, Chiara Rolando, Fabio Moda, Gianni Pezzoli, Iza K Radecka, Graziella Cappelletti.

  Poly-γ-glutamic acid (γ-PGA) is a bacterial-derived natural biopolymer that has gathered significant interest due to its antioxidant, anti-inflammatory, and neuroprotective properties. These characteristics make γ-PGA a potential candidate for the treatment of neurodegenerative diseases. In Parkinson's disease (PD), whose key pathological feature is the accumulation of neuronal α-synuclein aggregates, astrocytes, in addition to microglia, play a crucial role in clearing these aggregates; however, their capacity is limited. Overwhelmed astrocytes trigger an inflammatory response that exacerbates neurodegeneration. Therefore, strategies aimed at regulating the uptake of extracellular α-synuclein aggregates by astrocytes and mitigating inflammation could hold therapeutic promise. This work aimed to investigate the potential of γ-PGA in preventing or reversing the toxicity and inflammatory response induced by pre-formed α-synuclein fibrils (PFFs) in murine cortical astrocytes. Cell viability assays demonstrated that γ-PGA can counteract the toxicity induced by α-synuclein PFFs. Confocal microscopy and 3D reconstruction analyses revealed that γ-PGA colocalizes with PFFs, leading to a reduction in the uptake of these aggregates by astrocytes and a subsequent decrease in their inflammatory response. Consequently, γ-PGA emerges as a promising candidate for further investigation in the therapeutic management of PD.

Keywords:  Astrocytes; Fibrils; Inflammation; Parkinson's disease; Poly-γ-glutamic acid (γ-PGA); α-Synuclein

DOI:  https://doi.org/10.1016/j.ijbiomac.2025.145303
FEBS Lett. 2025 Jun 17.

Purification tags markedly affect self-aggregation of CPEB3.

Harunobu Saito, Yujin Lee, Motoharu Ueno, Naotaka Sekiyama, Masatomo So, Ayako Furukawa, Kenji Sugase.

  Since protein aggregation-including liquid-liquid phase separation (LLPS) and amyloid fibril formation-plays a critical role in both diseases and biological functions, understanding the mechanisms underlying protein aggregation is essential. Recombinant proteins are commonly used in vitro to investigate protein aggregation processes. However, if the purification tags remain uncleaved, they may affect the results and hinder accurate interpretation. Our findings demonstrate that the His6-GFP and His12 tags significantly affect liquid droplet and amyloid fibril formation in the intrinsically disordered region (IDR) of mouse cytoplasmic polyadenylation element-binding protein 3 (CPEB3) and its fragments. This study shows that the purification tags significantly affect aggregation assays, making it essential to account for their influence to accurately interpret protein aggregation.

Keywords:  CPEB3; His tag; IDR; LLPS; amyloid fibril; protein aggregation

DOI:  https://doi.org/10.1002/1873-3468.70090
Proteins. 2025 Jun 14.

Allium sativum-Derived Alliin and Allicin Stably Bind to α-Synuclein and Prevent Its Cytotoxic Aggregation.

S Rehan Ahmad, Md Zeyaullah, Abdullah M AlShahrani, Khursheed Muzammil, Adam Dawria, Md Faruque Ahmad, Ahmed Salih.

  Neurodegenerative diseases such as Parkinson's disease are characterized by the pathological aggregation of α-synuclein. Targeting α-synuclein aggregation through natural bioactive compounds offers a promising therapeutic strategy. In this study, sulfur-containing compounds derived from Allium sativum were evaluated for their drug-likeness, pharmacokinetic properties, and ability to inhibit α-synuclein aggregation using a combination of in silico and in vitro approaches. ADMET profiling indicated high gastrointestinal absorption for nine compounds, supporting their drug-like properties. Six compounds were predicted to cross the blood-brain barrier, suggesting potential efficacy in the central nervous system. Molecular docking identified alliin, allicin, E-ajoene, and diallyl disulfide as top binders to α-synuclein, forming stable interactions with key aggregation-prone regions. Molecular dynamics simulations over 100 ns confirmed the structural stability of alliin- and allicin-α-synuclein complexes, with minimal residue fluctuations and persistent hydrogen bonding. MM-GBSA binding energy analysis corroborated these results, showing favorable binding free energies, particularly for alliin and E-ajoene. Principal component analysis (PCA) further supported the role of alliin in stabilizing α-synuclein dynamics. In vitro cellular assays further validated these computational findings. Using an SH-SY5Y cell-based α-synuclein aggregation model, treatment with alliin and allicin significantly reduced α-synuclein aggregation. Furthermore, MTT-based cytotoxicity assays in SH-SY5Y neuroblastoma cells overexpressing α-synuclein revealed that alliin and allicin conferred notable cytoprotective effects by reducing α-synuclein-induced toxicity. Taken together, these findings highlight alliin and allicin as potent lead compounds that not only bind and stabilize α-synuclein but also attenuate its aggregation and associated cytotoxicity.

Keywords:  alliin and allicin; neuroprotection; parkinson's disease; phyto‐bioactive compounds; α‐synuclein aggregation

DOI:  https://doi.org/10.1002/prot.70000
PLoS Comput Biol. 2025 Jun;21(6): e1013155

Proteostasis signatures in human diseases.

Christine M Lim, Michele Vendruscolo.

The protein homeostasis (proteostasis) network maintains the proteome in a functional state. Although this network has been comprehensively mapped, its perturbations in disease remain incompletely characterised. To address this problem, here we define the proteostasis signatures, which represent the characteristic patterns of change in the proteostasis network associated with disease. We performed a large-scale, pan-disease analysis across 32 human diseases spanning 7 disease types. We first identified unique proteostasis perturbations in specific disease states. We then uncovered distinctive signatures differentiating disease types, pointing to a range of proteostasis mechanisms in disease development. Next, we tracked the temporal evolution of proteostasis signatures, revealing shifts in proteostasis disruption over the course of disease progression. Finally, we demonstrated how smoking, a major risk factor for many diseases, impairs proteostasis in a manner similar to disease, potentially creating a predisposed environment for disease onset. These results illustrate the opportunities offered by the study of human diseases from the perspective of proteostasis signatures.

DOI: https://doi.org/10.1371/journal.pcbi.1013155
Nat Commun. 2025 Jun 17. 16(1): 5328

Aneuploidy-induced proteostasis disruption impairs mitochondrial functions and mediates aggregation of mitochondrial precursor proteins through SQSTM1/p62.

Prince Saforo Amponsah, Jan-Eric Bökenkamp, Olha Kurpa, Svenja Lenhard, Anna Myronova, Daniel Osmar Vega Velazquez, Celina Hirschelmann, Christian Behrends, Johannes M Herrmann, Markus Räschle, Zuzana Storchová.

Aneuploidy, or aberrant chromosomal content, disrupts cellular proteostasis through altered expression of numerous proteins. Aneuploid cells accumulate SQSTM1/p62-positive cytosolic bodies, exhibit impaired protein folding, and show altered proteasomal and lysosomal activity. Here, we employ p62 proximity- and affinity-based proteomics to elucidate p62 interactors in aneuploid cells and observe an enrichment of mitochondrial proteins. Increased protein aggregation and colocalization of p62 with both novel interactors and mitochondrial proteins is further confirmed by microscopy. Compared to parental diploids, aneuploid cells suffer from mitochondrial defects, including perinuclearly-clustered mitochondrial networks, elevated reactive oxygen species levels, reduced mitochondrial DNA abundance, and impaired protein import, leading to cytosolic accumulation of mitochondrial precursor proteins. Overexpression of heat shock proteins in aneuploid cells mitigates protein aggregation and decreases the colocalization of p62 with the mitochondrial protein TOMM20. Thus, proteotoxic stress caused by chromosome gains results in the sequestration of mitochondrial precursor proteins into cytosolic p62-bodies, thereby compromising mitochondrial function.

DOI: https://doi.org/10.1038/s41467-025-60857-4
Mini Rev Med Chem. 2025 Jun 18.

Recent Progress of Small-molecule Inhibitors of O-GlcNAcase for Alzheimer's Disease.

Sheng Sun, JinFa Cao, Shujie Ji, Jian Wang.

  O-GlcNAcylation is a non-canonical form of protein glycosylation that occurs in nuclear, cytoplasmic, and mitochondrial proteins among all multicellular eukaryotes. There are only two enzymes that regulate this post-translational modification, one of which is O-GlcNAcase, a glycoside hydrolase that catalyzes the hydrolytic cleavage of O-GlcNAc from protein substrates. Related studies have shown that the reduction of O-GlcNAc levels is closely related to Alzheimer's disease, which is maintained by reducing the aggregation of tau via inhibiting O-GlcNAcase. Various smallmolecule O-GlcNAcase inhibitors with different chemical structures have been developed and used as chemical probes to explore the O-GlcNAc pathway. Although many reported inhibitors have shown that O-GlcNAcase activity has single-digit nmol IC50 values in binding assays, and molecules, such as LY-3372689, have entered phase II clinical studies, further exploration of novel OGlcNAcase inhibitors with higher inhibitory activity and specificity is still worthy of attention. This article reviews the pathogenesis and therapeutic role of O-GlcNAcase in Alzheimer's disease, as well as the recent progress of O-GlcNAcase small molecule inhibitors, including sugar-derived or non-sugar scaffolds, and summarizes the clinical progress and potential prospects of O-GlcNAcase inhibitors.

Keywords:  Alzheimer's disease; OGA; nonsugar inhibitors; small molecule.; sugar-derived inhibitors; tau

DOI:  https://doi.org/10.2174/0113895575376839250606183944
Hum Mol Genet. 2025 Jun 16. pii: ddaf091. [Epub ahead of print]

Calcium homeostasis modulator 2 aggravates α-synuclein-induced neurotoxicity in Parkinson's disease by activating PARP-1 depended Parthanatos.

Qi Pan, Huanjun Xu, Zongyu Xiao, Guanghao Liu, Huaming Zhang, Yiying Li.

   BACKGROUND: Parkinson 's disease (PD) is a common neurodegenerative disease. Aggregates formed by α-synuclein (α-Syn) are the main pathological changes of PD. In this study, the effects of Calcium homeostasis modulator 2 (Calhm2) on α-syn-induced neurotoxicity in PD were evaluated.
METHODS: Primary neurons were treated with α-Syn PFF to mimic the PD cellular model. Genes and proteins were evaluated utilizing RT-qPCR, Western blot and immunofluorescence, respectively. Cell damage was assessed using CCK-8 and LDH assay. Cellular oxidative stress was assessed via the detection of SOD, GSH and ROS level. Mitochondrial membrane potential, ATP level, AIF nuclear translocation and intracellular Ca2+ were determined for the assessment of Parthanatos. HE and immunofluorescence of TH and NeuN was detected pathological changes in vivo.
RESULTS: α-Syn PFF administration greatly resulted in oxidative stress, calcium overload and PARP-1 dependent Parthanatos in primary neurons. Following α-Syn PFF administration, Calhm2 and Calhm3, key calcium homeostasis modulator (Calhm) proteins, were markedly elevated in neurons, while Calhm1 expression exhibited a little change. In addition, suppression of Calhm2 obviously mitigated α-Syn PFF-induced oxidative stress injury, calcium overload and PARP-1 dependent Parthanatos in vitro. Similarly, in vivo results demonstrated that α-Syn PFF treatment led to PARP-1-dependent Parthanatos and nerve injury, while these effects were reversed by Calhm2 knockdown.
CONCLUSION: Calhm2 repression lightened α-Syn aggregation-induced neurotoxicity and PARP-1-dependent Parthanatos in PD, providing a novel therapeutic target for PD treatment.

Keywords:  Calcium homeostasis modulator 2; PARP-1; Parkinson’s disease; Parthanatos; α-synuclein

DOI:  https://doi.org/10.1093/hmg/ddaf091
Sci Adv. 2025 Jun 20. 11(25): eadu6050

Differential pathological dynamics triggered by distinct Parkinson patient-derived α-synuclein extracts in nonhuman primates.

R Kinet, M Bourdenx, S Dovero, M Darricau, M-L Arotcarena, S Camus, G Porras, M-L Thiolat, I Trigo-Damas, S Bohic, M Morari, E Doudnikoff, M Goikoetxea, S Claverol, C Tokarski, N Kruse, B Mollenhauer, C Estrada, N Garcia-Carrillo, M T Herrero, M Vila, J A Obeso, E Bezard, B Dehay.

The presence of α-synuclein (α-syn) aggregates, such as Lewy bodies in patients with Parkinson's disease (PD), contributes to dopaminergic cell death. Injection of PD patient-derived α-syn in nonhuman primates has illustrated the exquisite vulnerability of primate dopaminergic neurons. Here, we aimed to elucidate the temporal and spatial pathological changes induced by two distinct α-syn pathogenic structures, having large or small sizes. To unravel the underlying molecular pathways, we conducted a proteomic analysis of the putamen and the entorhinal cortex, two brain regions carrying notable α-syn pathology. We demonstrate that distinct assemblies of α-syn aggregates drive unique pathogenic changes that ultimately result in a comparable extent of nigrostriatal degeneration at the level of nigral dopaminergic neuron cell bodies and striatal dopaminergic terminals. More broadly, our findings identify pathogenic trajectories associated with large or small α-syn aggregates, suggesting the existence of several possible concomitant pathogenic routes in PD.

DOI: https://doi.org/10.1126/sciadv.adu6050
Commun Chem. 2025 Jun 14. 8(1): 186

A mechanistic model of pure and lipidic α-synuclein aggregation for advancing Parkinson's therapies.

Elena Righetti, Luca Marchetti, Enrico Domenici, Federico Reali.

Alpha-synuclein (aSyn) plays a crucial role in Parkinson's disease, with various aggregates proposed as pathogenic triggers and therapeutic targets. However, anti-aSyn aggregation compounds often fail due to limited knowledge of the underlying molecular basis. In particular, interactions with lipid membranes are central to both physiological and pathological roles of aSyn, yet their underlying mechanisms remain unclear. Disrupting this balance may drive Parkinson's onset and progression, underscoring the need for a mechanistic understanding of pure and lipid-mediated aggregation. Building on well-established in vitro aggregation studies, we propose a mathematical model of aSyn accumulation incorporating both aggregation routes via a nucleation-conversion-polymerization process with self-amplifying loops and toxic oligomers. Model calibration uses data from in vitro assays mimicking physiologically relevant conditions, providing insights into transient and stable aSyn intermediates. Incorporating aSyn-lipid interactions enables in silico exploration of how lipid-to-aSyn ratio influences aggregation, with possible implications for neurodegeneration. Sensitivity analysis highlights secondary nucleation inhibition as a potential anti-aggregation strategy. Overall, our work contributes to a unified framework for investigating in vitro aSyn aggregation and evaluating Parkinson's therapies by building on existing models. It can serve as a stand-alone tool and a modular component in multiscale models, with potential applications in quantitative systems pharmacology.

DOI: https://doi.org/10.1038/s42004-025-01558-3
Alzheimers Dement. 2025 Jun;21(6): e70363

A hypothesis explaining Alzheimer's disease, Parkinson's disease, and dementia with Lewy bodies overlap.

Victor Z Lau, Ifeoluwa O Awogbindin, Dan Frenkel, Shawn N Whitehead, Marie-Ève Tremblay.

  Lewy body-involving diseases (LBD) are commonly associated with Parkinson's disease (PD) featuring voluntary movement inhibition, due to dopaminergic neuron dysfunction in the substantia nigra. PD is clinically tracked through Lewy bodies (LB), composed of insoluble α-synuclein aggregates sequestered with organelles, particularly inside neurons. However, α-synuclein pathology also appears in incidental LBD, Parkinson's disease dementia, and dementia with LB (DLB). Incomplete explanations address how these clinical pathologies interrelate, LBD etiology variability, and frequently overlapping α-synuclein and Alzheimer's disease (AD) pathologies. We hypothesize that (1) chronic environmental insult exposure and (2) senescence(-like) neuron accumulation contribute toward initiating and sustaining LBD; individual cell vulnerability determines either cell reactivity, death, or senescence in response to environmental insults. We predicate that parkinsonian and other neurodegenerative symptoms over LBD progression involve (3) co-occurring AD pathologies, wherein dementia symptomology develops when synergistic glial senescence, tau hyperphosphorylation, and possible α-synuclein aggregation reach into regions involved in AD progression. HIGHLIGHTS: Senescence burden is predicted to explain α-synucleinopathy progression. Senescence and cell death are hypothesized to occur in α-synucleinopathies. Sub-apoptotic stress is proposed to induce senescence in α-synucleinopathies. Neuronal senescence likely first spreads α-synucleinopathies to new regions. Glial senescence likely underlies Parkinson's disease and Alzheimer's disease overlap.

Keywords:  Alzheimer's disease; Parkinson's disease; Parkinson's disease dementia; alpha‐synuclein; astrocytes; cellular senescence; dementia with Lewy bodies; microglia; neurons

DOI:  https://doi.org/10.1002/alz.70363