bims-proned Biomed News
on Proteostasis in neurodegeneration
Issue of 2025–02–16
eightteen papers selected by
Verena Kohler, Umeå University
  1. Sulfamerazine as a Potential Modulator against α-Synuclein Aggregation and Associated Toxicity.
  2. Modulation of conformational integrity and aggregation propensity of α-synuclein by osmolytes: Implications in therapeutic intervention of Parkinson's disease.
  3. Factors responsible for alpha-Synuclein aggregation.
  4. Multimer Detection System: A Universal Assay System for Differentiating Protein Oligomers from Monomers.
  5. Long non-coding RNAs as key regulators of neurodegenerative protein aggregation.
  6. Recent Advances in Co-Condensation and Co-Aggregation of Amyloid Proteins Linked to Neurodegenerative Diseases.
  7. Strategies for inhibiting amyloid fibrillation: Current status and future prospects.
  8. Unveiling the significance of synaptic proteins in parkinson's pathogenesis: A review.
  9. Roles of Ubiquitin Ligases and Deubiquitylases in Alzheimer's Disease.
  10. Proteolytic therapeutic modalities for amyloidoses: Insights into immunotherapy, PROTAC, and photo-oxygenation.
  11. Regulation of the structural dynamics, aggregation, and pathogenicity of polyQ-expanded Huntingtin by osmolytes.
  12. Kinetics of Amyloid Oligomer Formation.
  13. Single-Molecule Insight Into α-Synuclein Fibril Structure and Mechanics Modulated by Chemical Compounds.
  14. Altered ATP13A2/PARK9 Levels Influence α-Synuclein Accumulation in Neurons via Phagocytosis and Secretion in Glial Cells.
  15. Listerin promotes α-synuclein degradation to alleviate Parkinson's disease through the ESCRT pathway.
  16. Perillaldehyde Improves Parkinson-Like Deficits by Targeting G3BP Mediated Stress Granule Assembly in Preclinical Models.
  17. Protein misfolding: understanding biology to classify and treat synucleinopathies.
  18. ALZ-801 prevents amyloid β-protein assembly and reduces cytotoxicity: A preclinical experimental study.
  1. ACS Chem Neurosci. 2025 Feb 12.
    Sulfamerazine as a Potential Modulator against α-Synuclein Aggregation and Associated Toxicity.
    Priyanka Singh, Nagesh Y Kadam, Rajlaxmi Panigrahi, Arpit Mehrotra, Krishna Upadhayay, Madhumita Dey, Arpit Tyagi, Muhammad Aquib, Janni Nielsen, Giulia Kleijwegt, Prashant Singh, Abhishek Sharma, Alka Rao, Daniel E Otzen, Ashutosh Kumar, Deepak Sharma.
      Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder. The presence of Lewy bodies, primarily consisting of amyloid aggregates of the protein α-synuclein (α-Syn), is a common feature seen in dopaminergic neurons in (PD) patients. In the present study, we screened 2320 FDA-approved drugs and found 3 lead molecules, sulfamerazine, lathosterol, and tamoxifen, that reproducibly inhibited α-Syn fibrillation. Dose-response studies showed that sulfamerazine and lathosterol are relatively more potent than tamoxifen in inhibiting α-Syn aggregation. Among the lead compounds, sulfamerazine showed a significant reduction in α-Syn aggregation and associated toxicity in Caenorhabditis elegans model of PD. Sulfamerazine also reduced the accumulation of α-Syn aggregates in neuronal SH-SY5Y cells. Microscale thermophoresis confirmed the binding of sulfamerazine to α-Syn. NMR studies corroborated the binding of sulfamerazine with α-Syn and show that upon interaction, α-Syn is sequestered into large soluble dispersed assemblies, which is similar to as seen in transmission electron microscopy. We conclude that sulfamerazine and its derivatives hold promise as therapeutic agents against Parkinson's disease.
    Keywords:  Caenorhabditis elegans model of PD; Parkinson’s disease; SH-SY5Y cells; amyloid aggregates; sulfamerazine; α-synuclein
    DOI:  https://doi.org/10.1021/acschemneuro.4c00803
  2. Prog Mol Biol Transl Sci. 2025 ;pii: S1877-1173(24)00211-4. [Epub ahead of print]211 63-87
    Modulation of conformational integrity and aggregation propensity of α-synuclein by osmolytes: Implications in therapeutic intervention of Parkinson's disease.
    Ishfaq Ahmad Ahanger, Ishfaq Bashir Hajam, Owais Hassan Wani.
      Understanding the factors capable of modulation of conformational stability and aggregation propensity of α-synuclein (α-Syn), a hallmark of Parkinson's disease (PD), is crucial for developing future therapeutic interventions for this disease. This chapter aims at exploring the roles of osmolytes in affecting the structural dynamics of α-Syn as well as focuses on how these osmolytes impact folding, stability, and aggregation behavior of this important intrinsically disordered protein. A number of potent osmolytes, including trimethylamine N-oxide (TMAO), trehalose, myo-inositol, taurine, glycine, glutamate, and glycerol were discussed along with their overall effect on α-Syn. These osmolytes can stabilize native conformations or promote alternative folding pathways, thereby influencing α-Syn aggregation. The chapter highlights the dual role of osmolytes in either preventing or exacerbating aggregation, depending on their concentration and interaction mechanism with α-Syn. Moreover, by integrating current research results, the chapter provides insights into how osmolytes might be utilized for therapeutic interventions with potential avenues for managing PD. Overall, the chapter underscores the significance of osmolyte-induced modulation of α-Syn aggregation in the context of PD and highlights future research areas in this direction.
    Keywords:  Chemical chaperones; Osmolytes; Osmotic stress; Parkinson’s disease; Protein aggregation; Proteinopathies
    DOI:  https://doi.org/10.1016/bs.pmbts.2024.10.006
  3. Prog Mol Biol Transl Sci. 2025 ;pii: S1877-1173(24)00215-1. [Epub ahead of print]211 271-292
    Factors responsible for alpha-Synuclein aggregation.
    Khuraijam Surjalal Singh, Rahul Verma, Nagendra Singh, Laishram Rajendrakumar Singh, Akshita Gupta.
      Aggregation of α-Synuclein (α-Syn) is the hallmark of the pathophysiology of Parkinson's disease. Apart from aggregates, α-Syn can exist in multiple abnormal forms such as oligomers, protofibrils, fibrils amorphous aggregates etc. These forms initiate aggressive, selective and progressive neuronal atrophy through various modes such as mitochondrial dysfunction, lysosomal malfunction, and disruption of calcium homeostasis in various α-Syn-related neurodegenerative disorders. Structurally α-Syn is divided into three domains: N-terminal region made by amino acids1-67 (amphipathic, lysine-rich and interacts with acidic lipid membranes), Non-amyloid-β component (NAC) region made by amino acids 67-95 (hydrophobic region, central to α-syn aggregation) and C-terminal region made by amino acids 96-140 (acidic and proline-rich region responsible for interaction with other proteins). α-Syn follows the pattern of a typical intrinsically disordered protein and lacks a proper folded conformation and exist majorly in a random coil form, though on lipid binding the protein assumes an α-helical structure. The central random coil region of α-Syn is involved in fibril formation transforming into β-sheet rich secondary structures which is a characteristic of amyloids. This chapter entails an elaborate explanation of factors influencing the structure, function and aggregation of α-Syn. Major factors being abnormally high physiological expression of the protein, mutations, posttranslational modifications and also interactions with small molecules such as osmolytes in the cellular milieu. Studying the factors responsible for misfolding and aggregation of α-Syn along with the mechanism involved is crucial to understanding their implications in Parkinson's disease, and will yield valuable insights into disease mechanisms, potential therapeutic strategies.
    Keywords:  Aggregation; Mutations; Osmolytes; Post-translational modifications; α-Synuclein
    DOI:  https://doi.org/10.1016/bs.pmbts.2024.11.004
  4. Int J Mol Sci. 2025 Jan 30. pii: 1199. [Epub ahead of print]26(3):
    Multimer Detection System: A Universal Assay System for Differentiating Protein Oligomers from Monomers.
    Angelo Moscoso Jamerlan, Kyu Hwan Shim, Niti Sharma, Seong Soo A An.
      Depositions of protein aggregates are typical pathological hallmarks of various neurodegenerative diseases (NDs). For example, amyloid-beta (Aβ) and tau aggregates are present in the brain and plasma of patients with Alzheimer's disease (AD); α-synuclein in Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA); mutant huntingtin protein (Htt) in Huntington's disease (HD); and DNA-binding protein 43 kD (TDP-43) in amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and limbic-predominant age-related TDP-43 encephalopathy (LATE). The same misfolded proteins can be present in multiple diseases in the form of mixed proteinopathies. Since there is no cure for all these diseases, understanding the mechanisms of protein aggregation becomes imperative in modern medicine, especially for developing diagnostics and therapeutics. A Multimer Detection System (MDS) was designed to distinguish and quantify the multimeric/oligomeric forms from the monomeric form of aggregated proteins. As the unique epitope of the monomer is already occupied by capturing or detecting antibodies, the aggregated proteins with multiple epitopes would be accessible to both capturing and detecting antibodies simultaneously, and signals will be generated from the oligomers rather than the monomers. Hence, MDS could present a simple solution for measuring various conformations of aggregated proteins with high sensitivity and specificity, which may help to explore diagnostic and treatment strategies for developing anti-aggregation therapeutics.
    Keywords:  multimer detection system; neurodegenerative disease; oligomerization; protein aggregates
    DOI:  https://doi.org/10.3390/ijms26031199
  5. Alzheimers Dement. 2025 Feb;21(2): e14498
    Long non-coding RNAs as key regulators of neurodegenerative protein aggregation.
    Qi Xu, Dan Liu, Ling-Qiang Zhu, Ying Su, He-Zhou Huang.
      The characteristic events in neurodegenerative diseases (NDDs) encompass protein misfolding, aggregation, accumulation, and their related cellular dysfunction, synaptic function loss. While distinct proteins are implicated in the pathological processes of different NDDs, the process of protein misfolding and aggregation remains notably similar across various conditions. Specifically, proteins undergo misfolding into beta-folded (β-folded) conformation, resulting in the formation of insoluble amyloid proteins. Despite advancements in comprehending protein aggregation, certain facets of this intricate process remain incompletely elucidated. In recent years, the concept that long non-coding RNAs (lncRNAs) contribute to protein aggregation has gained recognition. LncRNAs influence the formation of protein aggregates by facilitating protein overexpression through the regulation of gene transcription and translation, inhibiting protein degradation via lysosomal and autophagic pathways, and targeting aberrant modifications and phase transitions of proteins. A better understanding of the relationship between lncRNAs and aberrant protein aggregation is an important step in dissecting the underlying molecular mechanisms and will contribute to the discovery of new therapeutic targets and strategies. HIGHLIGHTS: NDDs are marked by protein misfolding, aggregation, and accumulation, leading to cellular dysfunction and loss of synaptic function. Despite different proteins being involved in various NDDs, the process of misfolding into β-folded conformations and forming insoluble amyloid proteins is consistent across conditions. The role of lncRNAs in protein aggregation has gained attention, as they regulate gene transcription and translation, inhibit protein degradation, and target aberrant protein modifications. Understanding the link between lncRNAs and protein aggregation is crucial for uncovering molecular mechanisms and developing new therapeutic targets.
    Keywords:  long non‐coding RNA (lncRNA); neurodegenerative disease; protein aggregation
    DOI:  https://doi.org/10.1002/alz.14498
  6. Curr Protein Pept Sci. 2025 Feb 10.
    Recent Advances in Co-Condensation and Co-Aggregation of Amyloid Proteins Linked to Neurodegenerative Diseases.
    Xuefeng Zhang, Yujie Chen, Yuan Tan, Tong Pan, Guanghong Wei.
      The misfolding and aggregation of amyloid proteins are closely associated with a range of neurodegenerative diseases. Liquid-liquid phase separation (LLPS) can initiate the aggregation of proteins, indicating that LLPS may serve as an alternative pathway for the pathological aggregation of amyloid proteins. The co-occurrence of two or more amyloid pathologies has been observed in extensive pathophysiological studies and is linked to faster disease progression. The co- LLPS (also known as co-condensation) and co-aggregation of different disease-related proteins have been proposed as a potential molecular mechanism for combined neuropathology. Here, we reviewed the current state of knowledge regarding the co-aggregation and co-condensation of various amyloid proteins, including Aβ, tau, α-synuclein, TDP-43, FUS, and hnRNPA/B protein family, C9orf72 dipeptide repeats and prion protein. We briefly introduced the epidemiological correlation among different neurodegenerative diseases and specifically presented recent experimental findings about co-aggregation and co-condensation of two different amyloid proteins. Additionally, we discussed computational studies focusing on the molecular interactions between amyloid proteins to offer mechanistic insights into the co-LLPS and co-aggregation processes. This review provides an overview of the synergistic interactions between different disease-related proteins, which is helpful for understanding the mechanisms of combined neuropathology and developing targeted therapeutic strategies.
    Keywords:  Neurodegenerative diseases; amyloid proteins; co-- condensation; co-aggregation; cross-seeding; liquid-liquid phase separation; molecular mechanism.
    DOI:  https://doi.org/10.2174/0113892037350729241129054701
  7. Prog Mol Biol Transl Sci. 2025 ;pii: S1877-1173(24)00191-1. [Epub ahead of print]211 145-168
    Strategies for inhibiting amyloid fibrillation: Current status and future prospects.
    Md Nadir Hassan, Murtaza Hussain, Rizwan Hasan Khan.
      One of the hallmarks of multiple neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases, is deposition of insoluble amyloid fibrils, which are toxic proteinaceous structures containing cross β-sheets. Several inhibitory strategies have been devised by researchers to impede or slow down the generation of such toxic species. Small compounds, peptides, and antibodies have been studied as possible inhibitors to interfere with key steps in amyloid production. Furthermore, adjusting environmental variables, such as temperature and pH have been known to impact the amyloid fibrillation process. Additionally, strategies are also available to reduce the possibility of protein misfolding so as to inhibit the subsequent development of fibrils, simply by stabilizing native protein conformations. It is very promising to develop targeted inhibitory therapies and comprehend the complexities of amyloid fibrillation in order to develop effective therapeutics to slow the progression of neurodegenerative disorders linked to misfolding and aggregation of proteins.
    Keywords:  Amyloids; Blockers; Neurodegeneration; Protein aggregation; Protein misfolding; Therapeutics
    DOI:  https://doi.org/10.1016/bs.pmbts.2024.09.001
  8. Int J Biol Macromol. 2025 Feb 07. pii: S0141-8130(25)01338-8. [Epub ahead of print] 140789
    Unveiling the significance of synaptic proteins in parkinson's pathogenesis: A review.
    Ritu Soni, Jigna Shah.
      Parkinson's disease (PD) is a progressive neurodegenerative disorder that leads to death of dopaminergic neurons and deficiency of dopamine. It is the second most common neurodegenerative disorder worldwide after Alzheimer's disease (AD). It is mostly prevalent in elderly people above age 60. Clinical manifestations of PD include motor symptoms like tremor, akinesia, rigidity and gait imbalance; whereas non-motor symptoms include impaired olfaction and GI dysfunction. Α-synuclein is the major pathological hallmark of PD pathology. It aggregates and leads to formation of fibrils and Lewy bodies. It is a pre-synaptic protein that normally governs synaptic vesicle recycling. However, its aberration leads to its aggregation. There are several other synaptic proteins besides α-synuclein, and they might also have a pathological role. These synaptic proteins include synucleins (beta-synuclein, gamma-synuclein), synaptophysin, synaptobrevin, synaptogyrin, synaptotagmin and synaptojanin. In this review, we aim to explore underlying pathological role of these proteins. Clearer insights into the role of these synaptic proteins might aid in identifying newer targets which subsequently leads to development of novel therapeutics that target progression of the disease.
    Keywords:  Beta-synuclein; Gamma-synuclein; Parkinson's disease; Synaptic proteins; α-Synuclein
    DOI:  https://doi.org/10.1016/j.ijbiomac.2025.140789
  9. Mol Neurobiol. 2025 Feb 11.
    Roles of Ubiquitin Ligases and Deubiquitylases in Alzheimer's Disease.
    Fengju Jia, Lin Fu.
      The mechanisms responsible for the accumulation of Aβ plaques and neurofibrillary tangles, composed of phosphorylated Tau protein, in Alzheimer's disease (AD) remain a mystery. Dysfunction of the ubiquitin-proteasome system (UPS) largely contributes to abnormal protein aggregation. A cascade of ubiquitinating enzymes promotes protein ubiquitination, while deubiquitylases (DUBs) regulate its reversal. Disruptions in ubiquitination and deubiquitination processes result in abnormal protein aggregation and the formation of inclusion bodies, ultimately leading to neuronal damage. Recent studies have highlighted the significant role of protein ubiquitination and deubiquitination in the pathogenesis of AD. E3 ubiquitin ligases, which facilitate protein ubiquitination, are beneficial for Aβ clearance, synaptic function, gap junction maintenance, mitophagy, and neuroinflammation. Conversely, DUBs, responsible for removing ubiquitin from substrate proteins, inhibit Aβ and Tau degradation while promoting neuroinflammation in neurons. This review provides a thorough overview of the involvement of E3 ubiquitin ligases and DUBs in AD, highlighting their diverse roles in aspects of pathophysiological processes.
    Keywords:  Alzheimer’s disease; Deubiquitylases; E3 ubiquitin ligases; Ubiquitination; Ubiquitin–proteasome system
    DOI:  https://doi.org/10.1007/s12035-025-04739-2
  10. Neurotherapeutics. 2025 Feb 11. pii: S1878-7479(25)00026-1. [Epub ahead of print] e00548
    Proteolytic therapeutic modalities for amyloidoses: Insights into immunotherapy, PROTAC, and photo-oxygenation.
    Mai Kuriyama, Chu Fan Wang, Tatsuya Nagase, Youhei Sohma, Motomu Kanai, Yukiko Hori, Taisuke Tomita.
      Amyloidoses, which are characterized by abnormal accumulation of amyloid proteins leading to organ dysfunction, represent a major therapeutic challenge. They include neurodegenerative diseases, such as Alzheimer disease (AD), tauopathies and synucleinopathies. Since amyloids are causative factors in these diseases, the importance of proteolytic methods to remove amyloid, such as immunotherapy and Proteolysis Targeting Chimera (PROTAC) technology, has been recognized. Immunotherapy removes target proteins by antibody-mediated reactions and is the most studied method in practical use for the treatment of AD. PROTAC is a small molecule that uses the ubiquitin-proteasome system to degrade intracellular target proteins and has demonstrated efficacy in clinical trials for other diseases. In addition, a new modality called photo-oxygenation has been developed. Photo-oxygenation is a method of selectively adding oxygen to amyloid using a photocatalyst, which is a small molecule compound that is activated by light. Studies both in vitro and in vivo have shown promising results in inhibiting amyloid aggregation and enhancing the clearance of amyloid proteins. In this review, we introduce and discuss these proteolytic modalities, and provide insights into potential future directions for the clinical application in amyloidoses.
    Keywords:  Amyloid-β; Immunotherapy; PROTAC; Photo-oxygenation; Tau; α-synuclein
    DOI:  https://doi.org/10.1016/j.neurot.2025.e00548
  11. Prog Mol Biol Transl Sci. 2025 ;pii: S1877-1173(24)00174-1. [Epub ahead of print]211 113-143
    Regulation of the structural dynamics, aggregation, and pathogenicity of polyQ-expanded Huntingtin by osmolytes.
    Alice Y Liu, Amala Mathew, Christopher Karim, Pierre Eshak, Kuang Yu Chen.
      Huntington Disease is an autosomal dominant neurodegenerative disease caused by expansion of the polymorphic trinucleotide CAG repeat of the HTT gene to code for an expanded glutamine track of the mutant Huntingtin protein (mHTT). Like other neurodegenerative diseases, symptomatic presentation of Huntington Disease is age-dependent or age-related. This age-dependent manifestation of an autosomal dominant disease trait underscores important and possibly priming role of age-related changes in cellular physiology that are conducive to disease presentation. Herein, we present studies on the effects of osmolytes on mHTT structuring and aggregation, vis-a-vis pathogenicity. We show that stabilizing polyol osmolytes, by their generic activity in promoting protein structuring and compaction, drive aggregation of the disordered mHTT protein and simultaneously inhibit their binding to and sequestration of key transcription factors for improved homeostasis and cell survival under stress. These and related observations in the literature give strong support to the notion that lower molecular weight and structurally dynamic forms of mHTT contribute importantly to disease pathogenesis. Aging is associated with important changes in the cell environment-disease protein accumulation, reduced hydration, and macromolecular crowding as examples. These changes have significant consequences on the structuring and pathogenicity of the disordered mHTT protein. A crowded and less hydrated aging cell environment is conducive to mHTT binding to and inhibition of cell regulatory protein function on the one hand, and in promoting mHTT aggregation on the other hand, to culminate in Huntington disease presentation.
    Keywords:  Aging and Hypohydration; IDP Structuring & Aggregation; Neurodegeneration; Osmolytes; PolyQ-huntingtin
    DOI:  https://doi.org/10.1016/bs.pmbts.2024.08.005
  12. Annu Rev Biophys. 2025 Feb 10.
    Kinetics of Amyloid Oligomer Formation.
    Jiapeng Wei, Georg Meisl, Alexander J Dear, Thomas C T Michaels, Tuomas P J Knowles.
      Low-molecular-weight oligomers formed from amyloidogenic peptides and proteins have been identified as key cytotoxins across a range of neurodegenerative disorders, including Alzheimer's disease and Parkinson's disease. Developing therapeutic strategies that target oligomers is therefore emerging as a promising approach for combating protein misfolding diseases. As such, there is a great need to understand the fundamental properties, dynamics, and mechanisms associated with oligomer formation. In this review, we discuss how chemical kinetics provides a powerful tool for studying these systems. We review the chemical kinetics approach to determining the underlying molecular pathways of protein aggregation and discuss its applications to oligomer formation and dynamics. We discuss how this approach can reveal detailed mechanisms of primary and secondary oligomer formation, including the role of interfaces in these processes. We further use this framework to describe the processes of oligomer conversion and dissociation, and highlight the distinction between on-pathway and off-pathway oligomers. Furthermore, we showcase on the basis of experimental data the diversity of pathways leading to oligomer formation in various in vitro and in silico systems. Finally, using the lens of the chemical kinetics framework, we look at the current oligomer inhibitor strategies both in vitro and in vivo.
    DOI:  https://doi.org/10.1146/annurev-biophys-080124-122953
  13. Adv Sci (Weinh). 2025 Feb 14. e2416721
    Single-Molecule Insight Into α-Synuclein Fibril Structure and Mechanics Modulated by Chemical Compounds.
    Xiang Li, Lulu Bi, Shenqing Zhang, Qianhui Xu, Wencheng Xia, Youqi Tao, Shaojuan Wu, Yanan Li, Weidong Le, Wenyan Kang, Dan Li, Bo Sun, Cong Liu.
      α-Syn fibrils, a key pathological hallmark of Parkinson's disease, is closely associated with disease initiation and progression. Several small molecules are found to bind or dissolve α-syn fibrils, offering potential therapeutic applications. Here, an innovative optical tweezers-based, fluorescence-combined approach is developed to probe the mechanical characteristics of α-syn fibrils at the single-molecule level. When subjected to axial stretching, local deformation within α-syn fibrils appeared at forces above 50 pN. These structural alternations occurred stepwise and are irreversible, suggesting unfolding of individual α-syn molecules or subdomains. Additionally, α-syn fibrils exhibits high heterogeneity in lateral disruption, with rupture force ranging from 50 to 500 pN. The impact of different compounds on the structure and mechanical features of α-syn fibrils is further examined. Notably, epigallocatechin gallate (EGCG) generally attenuates the rupture force of fibrils by wedging into the N-terminal polar groove and induces fibril dissociation. Conversely, copper chlorophyllin A (CCA) attaches to four different sites wrapping around the fibril core, reinforcing the stability of the fibril against rupture forces. The work offers an effective method for characterizing single-fibril properties and bridges compound-induced structural alternations with mechanical response. These insights are valuable for understanding amyloid fibril mechanics and their regulation by small molecules.
    Keywords:  chemical compounds; optical tweezers; parkinson's disease; single molecule; α‐synuclein fibril
    DOI:  https://doi.org/10.1002/advs.202416721
  14. Cells. 2025 Jan 22. pii: 163. [Epub ahead of print]14(3):
    Altered ATP13A2/PARK9 Levels Influence α-Synuclein Accumulation in Neurons via Phagocytosis and Secretion in Glial Cells.
    Taiji Tsunemi, Yuta Ishiguro, Asako Yoroisaka, Dou Feng, Nobutaka Hattori.
      (1) Background: Parkinson's disease (PD) is characterized by the pathological accumulation of α-synuclein (α-syn) containing Lewy bodies (LBs) and Lewy neurites (LNs) within neurons. Growing evidence indicates that α-syn may propagate throughout the nervous system in a manner similar to prion-like transmission. Extracellular vesicles (EVs) may contribute to this pathway. We and others have reported that ATP13A2/PARK9 deficiency results in decreased EVs while its overexpression leads to increased EV generation. For analyzing EV-mediated α-syn secretion in neighboring neurons, we planned to alter Atp13a2 levels in vivo. (2) Methods: Three months after inoculating mouse α-syn fibrils into the striatum of Atp13a2-null and wild-type mice, we stained brain sections with anti-phosphorylated α-syn antibodies and then quantified LBs/LNs. We also examined the effect of increased levels of ATP13A2 by injecting lentivirus carrying human ATP13A2. Finally, we used cultured astrocytes and microglia for α-syn uptake and release, which were mediated by EVs. (3) Results: While LBs/LNs were formed in the entire brains, no significant difference was observed in LB/LN formation between Atp13a2-deficient and wild-type mice. Interestingly, the overexpression of ATP13A2 led to decreased LB/LN formation in the entire brains. Microglia and astrocytes released EVs more than neurons. EVs released from microglia and astrocytes contained more α-syn PFFs than those from neurons. (4) Conclusions: These results suggest that enhanced EV secretion by increased ATP13A2 levels attenuate the spreading of α-syn in brains, suggesting a protective role of ATP13A2 in α-synucleinopathies.
    Keywords:  ATP13A2; Parkinson’s disease; extracellular vesicles
    DOI:  https://doi.org/10.3390/cells14030163
  15. Sci Adv. 2025 Feb 14. 11(7): eadp3672
    Listerin promotes α-synuclein degradation to alleviate Parkinson's disease through the ESCRT pathway.
    Fei Qin, Runyu Cao, Wenjing Cui, Xuemei Bai, Jiahua Yuan, Yuling Zhang, Yaxing Liu, Nan Cao, Na Dong, Min Zhou, Tian Chen, Feng Liu, Wanwei Sun, Yi Zheng, Wei Zhao, Bingyu Liu, Chengjiang Gao.
      Parkinson's disease (PD) is a neurodegenerative disorder characterized by the progressive accumulation of abnormal α-synuclein (α-syn) within dopaminergic neurons in the substantia nigra region of the brain. Despite excessive accumulation of α-syn being key to the pathogenesis of PD, the mechanisms governing its clearance remain elusive. In this study, we found that the endosomal sorting complex required for transport (ESCRT) system plays a crucial role in capturing and facilitating the degradation of ubiquitinated α-syn. The E3 ubiquitin ligase Listerin was found to promote K27-linked polyubiquitination of α-syn, directing it to the endosome for subsequent degradation. We showed that the deletion of the Listerin gene exacerbates the neurodegenerative progression in a mouse model of PD, whereas the overexpression of Listerin effectively mitigates disease progression in PD mice. Consequently, our study reveals a mechanism for α-syn degradation and identifies Listerin as a promising therapeutic target for the treatment of PD.
    DOI:  https://doi.org/10.1126/sciadv.adp3672
  16. Adv Sci (Weinh). 2025 Feb 14. e2412152
    Perillaldehyde Improves Parkinson-Like Deficits by Targeting G3BP Mediated Stress Granule Assembly in Preclinical Models.
    Minglv Fang, Lingling Luo, Youjia Chen, Ying Liu, Yingxuan Yan, Fei Wang, Yan Zou, Huanhu Zhu, Xiaojun Wu, Zhigang Jin, Cheng Huang, Yu Zhang, Shengjie Fan.
      Stress granules (SGs) fulfill a pivotal role in host defense mechanisms, by sequestering both mRNA and protein via the process of liquid-liquid phase separation (LLPS). In this study, we showed that perillaldehyde (PAE), a natural occurring compound, bound directly to the core protein of SGs, Ras GTPase-activating protein-binding protein 1/2 (G3BP1/2), thereby inducing the assembly of SGs through the LLPS of G3BP/RNA complexes in vitro. Moreover, in Parkinson's disease (PD) models using Caenorhabditis elegans (C. elegans) and mice, PAE administration prompted SG formation, enhanced eIF2α phosphorylation, shielded dopaminergic neurons from toxic insults, mitigated α-synuclein (α-syn) aggregation, and improved PD-like motor disorders. In addition, these findings revealed that the interaction between G3BP1 and histone deacetylase 6 (HDAC6) inhibited the functions of cytoplasmic HDAC6 and reduced α-syn aggregation in cells and worms. Notably, the inhibition of SG assembly via gtbp-1 and tiar-1 RNAi effectively counteracted the beneficial effects of PAE in C. elegans. Collectively, these results imply that PAE may exert neuroprotective effects by targeting G3BP-mediated SG formation, thereby safeguarding dopaminergic neurons from toxic damage.
    Keywords:  G3BP; Parkinson's disease; histone deacetylase 6; liquid–liquid phase separation; perillaldehyde; stress granules; α‐synuclein
    DOI:  https://doi.org/10.1002/advs.202412152
  17. J Neural Transm (Vienna). 2025 Feb 11.
    Protein misfolding: understanding biology to classify and treat synucleinopathies.
    Tiago Fleming Outeiro, Günter Höglinger, Anthony E Lang, Tuane C R G Vieira.
      Protein misfolding and aggregation is a major pathological hallmark in a variety of human conditions, including cancer, diabetes, and neurodegeneration. However, we still do not fully understand the role of protein accumulation in disease. Interestingly, recent breakthroughs in artificial intelligence (AI) are having a tremendous impact on our ability to predict three-dimensional protein structures and understand the molecular rules governing protein folding/misfolding. This progress will enable us to understand how intrinsic and extrinsic factors trigger protein misfolding, thereby changing protein function. These changes, in some cases, are related to normal biological responses and, in other cases, associated with pathological alterations, such as those found in many neurodegenerative disorders. Here, we provide a brief historical perspective of how findings in the field of prion diseases and prion biology have enabled tremendous advances that are now forming the basis for our understanding of disease processes and discuss how this knowledge is now emerging as central for our ability to classify, diagnose, and treat devastating neurodegenerative disorders such as Parkinson's and Alzheimer's diseases.
    Keywords:  Alpha-synuclein; Biomarkers; Disease classification; Neurodegeneration; Parkinson’s disease; Protein aggregation
    DOI:  https://doi.org/10.1007/s00702-025-02889-0
  18. FASEB J. 2025 Feb 15. 39(3): e70382
    ALZ-801 prevents amyloid β-protein assembly and reduces cytotoxicity: A preclinical experimental study.
    Daiki Muramatsu, Takahiro Watanabe-Nakayama, Mayumi Tsuji, Kenichi Umeda, Sadao Hikishima, Hiroto Nakano, Yasuhiro Sakashita, Tokuhei Ikeda, Hiroki Konno, Noriyuki Kodera, Toshio Ando, Moeko Noguchi-Shinohara, Kenjiro Ono.
      Alzheimer's disease (AD) is the most prevalent age-related neurodegenerative disorder, mainly characterized by amyloid β (Aβ) accumulation in the brain. Numerous new agents are currently undergoing clinical trials as disease-modifying therapies (DMTs) targeting Aβ. ALZ-801 is a promising candidate DMT for AD, with a phase 3 trial of ALZ-801 ongoing specifically for apolipoprotein E (APOE) ε4 homozygous patients with early-stage AD. This study aimed to examine the effects of ALZ-801 on Aβ assembly and explore its toxicological profile. Thioflavin T (ThT) assays and two imaging modalities-transmission electron microscopy (TEM) and high-speed atomic force microscopy (HS-AFM)-were used to evaluate ALZ-801's effects on Aβ assembly. To assess the effect of ALZ-801 on Aβ42-induced cytotoxicity, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays and lactate dehydrogenase (LDH) assays were performed. ThT assays revealed increased lag time and decreased fluorescence in the presence of ALZ-801, confirming inhibition of Aβ42 fibril formation, as confirmed by TEM. Real-time observation using HS-AFM revealed that ALZ-801 inhibited the formation of Aβ42 fibril from low-molecular-weight (LMW)-Aβ42 in the presence of Aβ42 seeds. HS-AFM also revealed that globular aggregates from LMW-Aβ42 were significantly larger with ALZ-801, with few fibrils noted. MTT and LDH assays indicated that ALZ-801 prevented LMW-Aβ42-induced cytotoxicity but did not reduce cytotoxicity induced by high-molecular-weight-Aβ42. ALZ-801 can inhibit Aβ42 aggregation by preventing both nucleus formation and fibril elongation, while promoting large globular oligomer formation, and can significantly reduce LMW-Aβ42-induced cytotoxicity. These findings underscore the potential of ALZ-801 as an effective DMT for APOE ε4 homozygous patients with AD.
    Keywords:  ALZ‐801; Alzheimer disease; amyloid beta‐peptides; apolipoproteins E; atomic force, microscopy; protein aggregates
    DOI:  https://doi.org/10.1096/fj.202402622R
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