bims-proned 2025-12-07 papers

bims-proned

Biomed News

on Proteostasis in neurodegeneration

Issue of 2025–12–07
ten papers selected by
Verena Kohler, Umeå University

Nucleolar aggregation of key neuropathological proteins in the postmortem neurodegenerative brain.
Precision Interdiction of α-Synuclein Folding Pathways by Molecular Tweezers.
Targeted tau protein degradation: a promising therapeutic approach for tauopathies.
Cardiolipin and mitochondrial membrane integrity in neurodegeneration: insights from α-synuclein-driven Parkinson's disease.
Macromolecular Crowding and Protein Aggregation: Friend, Foe or Contextual Force?
Differential microglial responses to structurally distinct alpha-synuclein polymorphs.
Targeting Liquid-Liquid Phase Separation and Autophagy in Alzheimer's Disease: Insights into Molecular Mechanisms and Therapeutic Potential.
HDAC6 Inhibition Reduces Seeded Tau and α-Synuclein Pathologies in Primary Neuron Cultures and Wild-type Mice.
Tetramethylpyrazine nitrone: a multifaceted neuroprotective agent in neurodegenerative disorders.
Lipid droplets promote the aberrant liquid-liquid phase separation of alpha-synuclein leading to impaired energy homeostasis.

Acta Neuropathol. 2025 Dec 03. 150(1): 60

Nucleolar aggregation of key neuropathological proteins in the postmortem neurodegenerative brain.

Guinevere F Lourenco, Maria Elizabeth Torres-Pacheco, YuHong Fu, Hongyun Li, Heather McCann, Claire E Shepherd, Jillian J Kril, Glenda M Halliday.

  Nucleolar disturbances have long been implicated in neurodegenerative diseases but, to date, aggregation and immobilization of proteins into nucleolar bodies have only been reported in vitro and in cell models, and only for amyloid β (Aβ). In model systems, these bodies have been shown to coordinate local nuclear protein synthesis with potential to seed diagnostic neuropathologies. Here we confirm the presence of nucleolar aggregates of amyloid nature in postmortem brain tissue from controls and patients with neurodegenerative pathologies and demonstrate the nucleolar sequestration of fibrillation-prone proteins associated with neurodegenerative diseases (Aβ, tau, α-synuclein, TDP-43, and FUS, but not prion or peptide repeats). We identified nucleolar bodies ranging from multiple small foci to a centralized, large amyloid aggresome, that appear to represent progressive stages of protein immobilization from liquid-like foci to the formation of nucleolar aggresomes. Neurons with nucleolar aggresomes were more vulnerable to neurodegeneration, decreasing in number with increasing duration of disease. Nucleolar aggresomes with phosphorylated tau correlated with increasing amounts of neuropathology, while phosphorylated TDP-43 in nucleolar aggresomes distinguished cases with limbic-predominant age-related TDP-43 encephalopathy. Nucleolar aggresomes containing α-synuclein occurred in a large proportion of aged controls with limited neuronal loss (potentially asserting neuroprotection). Other fibrillation-prone proteins were either absent (prion and peptide repeats) or found less commonly in nucleolar aggresomes (Aβ and FUS), and amyloidogenic nuclear proteins not screened in this study may also occur in nucleolar aggresomes. Our data do not support the concept that proteins in aggresomes seed diagnostic neuropathologies as there were no associations between their presence in nucleoli aggresomes and their cytoplasmic or extracellular accumulation. Assessment of neurons with and without phosphorylated tau or α-synuclein aggresomes showed that phosphorylated tau ameliorated the increased DNA levels found in AD. Collectively, our observations establish that nucleolar sequestration of amyloidogenic proteins is a common molecular mechanism in the brain, representing a novel contribution to the understanding of nucleolar protein aggregation in the context of neuroprotection and neurodegeneration during brain aging.

Keywords:  Neurodegeneration; Nucleolar aggregation; Nucleolar aggresomes; Nucleolar amyloid bodies; Nucleolar cavities; Nucleolar sequestration; Nucleolus

DOI:  https://doi.org/10.1007/s00401-025-02968-2
Biochemistry. 2025 Dec 04.

Precision Interdiction of α-Synuclein Folding Pathways by Molecular Tweezers.

Madhusmita Devi, Sandip Paul.

The misfolding of α-synuclein (α-Syn) is a pivotal event in the degeneration of dopaminergic neurons and the progression of Parkinson's disease. Given its pathological significance, elucidating the self-assembly of α-Syn and developing inhibitors that suppress aberrant misfolding are imperative for effective synucleinopathy therapies. Building upon the remarkable potential of Whitlock's caffeine-armed molecular tweezer in inhibiting amyloid-β aggregation, this study employs all-atom MD simulations under NPT conditions to explore its impact on α-Syn misfolding. Analyses of the secondary structure and cluster conformations reveal a global transition of the N-terminal and NAC regions into largely unstructured conformations interspersed with multiple β-sheet formations spanning both regions. The simulations further capture the emergence of a β-hairpin structure spanning residues 38-53, a region previously identified as the primary nucleation site for aggregation. Notably, the introduction of the caffeine-tweezers significantly reduces the formation of ordered β-sheet structures. Contact maps, free-energy landscapes, and binding evaluations collectively demonstrate a strong binding preference of the tweezer for the N- and C-terminal regions of the peptide. By engaging in π-stacking interactions with aromatic residues at the termini, the tweezer induces a looped conformation that disrupts non-native contacts between the N-terminus and the NAC segment. This rearrangement restores native long-range interactions between the terminal domains, thereby re-establishing the protein's intrinsic regulatory mechanism that suppresses NAC-mediated pathological aggregation. These findings elucidate the inhibitory role of the caffeine-tweezer, underscoring its therapeutic potential in targeting α-Syn misfolding. Our findings offer a rational framework for the design of novel therapeutics combating synucleinopathies.

DOI: https://doi.org/10.1021/acs.biochem.5c00519
Neuroscience. 2025 Dec 03. pii: S0306-4522(25)01139-X. [Epub ahead of print]

Targeted tau protein degradation: a promising therapeutic approach for tauopathies.

Narjes Baazaoui, Mohammad Y Alfaifi, Ali A Shati, Rania Ben Saad, Stefania Garzoli.

  Tauopathies are a spectrum of diseases characterized by the pathological aggregation of tau proteins. Several therapeutic strategies have been developed to treat or stop the progression of these diseases, but all have failed in clinical trials. One potential reason for these failures is that disease-causing proteins are resilient to treatment with conventional drugs since they lack a predefined monomeric structure and an active binding site. Tau is an intrinsically disordered protein; paradoxically, its flexible conformation makes it an ideal candidate for targeted protein degradation (TPD) approaches, which bypass the need for structured binding pockets by inducing proximity-based recruitment to degradative machinery. TPD uses bifunctional molecules to recruit proteins to the ubiquitin-proteasome system (UPS) or autophagy-lysosomal pathways, overcoming limitations of traditional small-molecule inhibitors (SMIs). As these technologies have been effective in degrading several disease-related proteins, they hold significant promise for treating tauopathies caused by protein aggregation. Herein, we review the tau structure and functions, summarize the main post-translational modifications (PTMs) of tau including those causing pathological aggregation of tau, the major degradative cellular machinery and their defects in pathological state, and discuss the advantages and current progress of targeted protein degradation strategies compared to traditional approaches.

Keywords:  Autophagy lysosomal pathway; Post-translational modifications; Targeted protein degradation; Tau; Tau aggregation; Tau seeding; Tauopathies; Ubiquitin–proteasome pathway

DOI:  https://doi.org/10.1016/j.neuroscience.2025.11.041
Acta Neuropathol Commun. 2025 Dec 03.

Cardiolipin and mitochondrial membrane integrity in neurodegeneration: insights from α-synuclein-driven Parkinson's disease.

Eva D Ruiz-Ortega, Anna Wilkaniec, Josué Juárez, Agata Adamczyk.

  Parkinson's disease (PD) is defined by the progressive loss of dopaminergic neurons and the accumulation of misfolded α-synuclein (α-syn), yet the molecular determinants of selective neuronal vulnerability remain unresolved. Increasing evidence implicates mitochondria-and particularly their membranes-as critical platforms where α-syn is toxic. This review highlights how α-syn engages mitochondrial membranes through two interconnected processes: classical aggregation and liquid‒liquid phase separation. Both pathways disrupt membrane architecture, compromise respiratory chain function, and impair mitophagy. A pivotal mediator of these events is cardiolipin (CL), a mitochondria-specific phospholipid essential for cristae organization and quality control pathways. Despite extensive progress, the precise mechanistic contributions of CL to α-syn aggregation, phase transitions, and neuronal degeneration remain poorly defined. Clarifying this interplay is crucial, as CL not only binds α-syn with high affinity but also determines whether it remains in a functional state or progresses toward toxic assemblies. By integrating recent advances, we propose a unifying perspective on CL as a molecular switch at the crossroads of mitochondrial biology, protein aggregation, and phase behavior. Beyond mechanistic insight, this view underscores the potential of CL as a target for the development of mitochondria-directed therapies in PD.

Keywords:  Alpha-synuclein; Cardiolipin; Liquid‒liquid phase separation; Mitochondrial dysfunction; Parkinson’s disease

DOI:  https://doi.org/10.1186/s40478-025-02190-x
Prog Biophys Mol Biol. 2025 Dec 02. pii: S0079-6107(25)00069-0. [Epub ahead of print]

Macromolecular Crowding and Protein Aggregation: Friend, Foe or Contextual Force?

Isabella V Gimón, Conner Sandefur, Santiago Schnell.

  Protein aggregation plays a dual role in cellular biology, enabling essential functions such as intracellular organization, signaling, and storage, while also contributing to pathological states associated with misfolding and toxicity. However, existing literature lacks an integrated framework for predicting when crowding will favor productive assembly versus drive pathological outcomes-a gap that has hindered both mechanistic understanding and therapeutic development. This review examines how macromolecular crowding-an intrinsic feature of the intracellular environment-shapes protein aggregation outcomes by modulating key physicochemical parameters: volume exclusion, electrostatic interactions, aggregate morphology, cytoplasmic viscosity, and liquid-liquid phase separation. We demonstrate that crowding acts not as a universal promoter or inhibitor of aggregation, but rather as a context-dependent modulator that amplifies latent vulnerabilities in proteins predisposed to misfolding while facilitating productive assembly in properly regulated systems. By analyzing the mechanistic continuum between functional and pathological aggregation, we provide a framework for interpreting how identical molecular forces yield divergent biological outcomes depending on protein properties, environmental conditions, and cellular regulation. This perspective clarifies how the intracellular milieu governs aggregation dynamics and identifies promising avenues for therapeutic intervention, including strategic modulation of crowding conditions to promote protective assemblies while suppressing toxic aggregates in misfolding-related diseases. We conclude by outlining future directions toward quantitative, predictive models that integrate molecular mechanism with physiological context, bridging the gap between in vitro biophysics and in vivo cellular function.

Keywords:  Amyloid Formation; Biomolecular Condensates; Electrostatic Interactions; Liquid-Liquid Phase Separation; Macromolecular Crowding; Protein Aggregation; Protein Misfolding; Volume Exclusion

DOI:  https://doi.org/10.1016/j.pbiomolbio.2025.12.001
Mol Brain. 2025 Dec 05.

Differential microglial responses to structurally distinct alpha-synuclein polymorphs.

Katherine Chang, Jina Kim, Michiyo Iba, Jae-Hyeon Park, Alexandria Beilina, Zulfeqhar A Syed, Valentina Baena, Liam Horan-Portelance, Mark R Cookson, Sungyong You, Changyoun Kim.

Synucleinopathies are age-related neurological disorders which include dementia with Lewy bodies (DLB), Parkinson's disease (PD), and multiple system atrophy (MSA). A hallmark of these diseases is the pathological accumulation of α-synuclein aggregates, along with sustained neuroinflammatory responses. Recent studies have demonstrated the existence of structurally distinct α-synuclein aggregates in this group of the diseases. While the correlation between specific forms of α-synuclein and distinct pathological characteristics has been extensively studied, their relationship to neuroinflammation remains elusive. Here, we examined the effects of structurally distinct α-synuclein polymorphs on microglial neuroinflammation. Human induced pluripotent stem cells (iPSCs)-derived microglia (iMicroglia, iMG) were treated with α-synuclein polymorphs including EGCG stabilized α-synuclein oligomers (EO), kinetically stable α-synuclein oligomers (KSO), dopamine stabilized α-synuclein oligomers (DO), α-synuclein preformed fibrils (PFF), sonicated α-synuclein preformed fibrils (sPFF), and matured α-synuclein fibrils (Fib). Microglial gene expressions were accessed by transcriptome analysis and Toll-like receptor agonist activities were determined by HEK-Blue TLR reporter assay. Exposures to kinetically stable α-synuclein oligomers and matured α-synuclein fibrils induced the expression of microglial cytokines and chemokines, while other species did not. Microglial transcriptome analysis yielded that all polymorphs commonly induce toll-like receptor (TLR) signaling cascade despite differential transcriptomic phenotypes. Among structurally distinct α-synuclein polymorphs, live cell TLR reporter assay showed that kinetically stable α-synuclein oligomers induce the activities of TLR2 and 4, and sonicated α-synuclein preformed fibril TLR4, relative to the control. These results suggest that structurally distinct α-synuclein polymorphs have likewise distinct neuroinflammatory properties.

DOI: https://doi.org/10.1186/s13041-025-01256-0
Neurochem Res. 2025 Dec 04. 51(1): 9

Targeting Liquid-Liquid Phase Separation and Autophagy in Alzheimer's Disease: Insights into Molecular Mechanisms and Therapeutic Potential.

Xiaopeng Li, Yan Liu, Hong Hu, Shenghong Li.

  Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the leading cause of dementia, marked by cognitive decline and memory loss. Its multifactorial etiology involves genetic, environmental, and cellular factors, with key pathological features including amyloid-beta (Aβ) plaques and tau tangles. Recent studies have highlighted the roles of liquid-liquid phase separation (LLPS) and autophagy in AD onset and progression. LLPS, an emerging biophysical phenomenon, facilitates protein aggregation and may contribute to early disease stages. Dysregulated autophagy results in the accumulation of toxic proteins, such as Aβ and tau, exacerbating neurodegeneration. This review explores the interplay between LLPS and autophagy in AD, a relationship often overlooked in the literature. It examines their biological mechanisms, synergistic effects on AD pathology, and potential therapeutic strategies. Additionally, we discuss the therapeutic potential of both natural and non-natural compounds in modulating LLPS and autophagy. While compounds like curcumin show promise, a comprehensive framework for their targeted use remains under development. This review provides theoretical support for the advancement of more precise AD therapies.

Keywords:  Alzheimer's disease; Amyloid-beta; Autophagy; Liquid-liquid phase separation; Tau aggregation

DOI:  https://doi.org/10.1007/s11064-025-04623-4
J Neurosci. 2025 Dec 02. pii: e1092252025. [Epub ahead of print]

HDAC6 Inhibition Reduces Seeded Tau and α-Synuclein Pathologies in Primary Neuron Cultures and Wild-type Mice.

Alex Crowe, Yuemang Yao, Mira Newman, Kevt'her Hoxha, Thallyah Baffic, Kurt R Brunden.

A previous compound screen identified two molecules with histone deacetylase 6 (HDAC6) inhibitory activity that reduced Alzheimer's disease (AD)-like tau inclusions in a primary rat cortical neuron model seeded with AD-brain derived tau fibrils. Testing here of additional HDAC6-selective inhibitors confirmed that compounds of this type decreased neuronal tau inclusions. Moreover, HDAC6 inhibitors also reduced Parkinson's disease (PD)-like α-synuclein aggregates in primary neurons seeded with recombinant α-synuclein fibrils. Knockdown of HDAC6 expression through treatment of seeded neuron cultures with AAV harboring HDAC6-specific shRNA also resulted in a reduction of tau and α-synuclein inclusions. Multiple compounds were evaluated for their ability to inhibit brain HDAC6 in mice, and ACY-738 was found to effectively inhibit brain HDAC6 activity upon oral dosing. ACY-738 was utilized in an efficacy study in which tau and α-synuclein pathologies were induced in wild-type mice through intracerebral injections of AD-brain derived tau and α-synuclein fibrils. Groups of male and female mice first received ACY-738 in drinking water one day prior to (pre-seeding) or one week after (post-seeding) brain injections of fibrils, followed by continued dosing for an additional 3 months. A control group of fibril-injected mice received water without ACY-738. Immunohistochemical evaluations revealed that ACY-738 administration resulted in significant reductions of tau pathology in both dosing schemes. Moreover, α-synuclein pathology was significantly reduced in mice with pre-seeding ACY-738 administration, with a strong trend toward reduction after post-seeding dosing. These results suggest that HDAC6 inhibitors have potential for the treatment of AD, PD and related diseases.Significance Statement The spread and abundance of brain tau pathology correlate with AD patient cognitive status, and there are presently no approved drugs that target tau. We demonstrate that HDAC6 inhibition or knockdown reduce both tau and α-synuclein inclusions that develop in wild-type rodent neuron models. A preferred HDAC6 inhibitor, ACY-738, was identified that inhibits brain HDAC6 when administered orally to mice. This compound was examined in a wild-type mouse model that develops concurrent seeded tau and α-synuclein brain inclusions. Significant reductions of both tau and α-synuclein inclusions were observed in mice dosed with ACY-738, suggesting that HDAC6 inhibition may be a therapeutic strategy for AD, PD and related diseases.

DOI: https://doi.org/10.1523/JNEUROSCI.1092-25.2025
Neurodegener Dis Manag. 2025 Dec 04. 1-15

Tetramethylpyrazine nitrone: a multifaceted neuroprotective agent in neurodegenerative disorders.

Eshak I Bahbah.

  Neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS) share key pathological features, including oxidative stress, mitochondrial dysfunction, and impaired protein homeostasis, yet remain without effective disease-modifying therapies. Tetramethylpyrazine nitrone (TBN), a synthetic derivative of tetramethylpyrazine bearing a free radical-scavenging nitrone moiety, has emerged as a promising multi-target neuroprotective agent. This review synthesizes preclinical and clinical data supporting TBN's therapeutic potential in AD, PD, and ALS. In AD models, TBN reduces amyloid-β accumulation and tau hyperphosphorylation, enhances autophagic clearance, preserves synaptic integrity, and improves cognitive performance. In PD models, TBN confers dopaminergic neuroprotection, restores motor function, and promotes α-synuclein degradation, effects mediated largely through activation of the PGC-1α/Nrf2 pathway and augmentation of the ubiquitin-proteasome system (UPS). In ALS models, TBN mitigates motor neuron loss, improves motor performance, and extends survival, likely via the PGC-1α/Nrf2/HO-1 axis and enhanced autophagic activity. Phase I studies have established TBN's favorable oral and intravenous pharmacokinetics, effective blood - brain barrier penetration, and overall safety and tolerability in healthy volunteers. Owing to its multi-pathway mechanism, principally engaging antioxidant/mitochondrial pathways and proteostasis (autophagy/UPS), TBN represents a compelling candidate for continued clinical development, either as monotherapy or in combination with disease-specific interventions.

Keywords:  PGC-1α/Nrf2 pathway; Parkinson’s disease; Tetramethylpyrazine nitrone; alzheimer’s disease; amyotrophic lateral sclerosis

DOI:  https://doi.org/10.1080/17582024.2025.2598227
bioRxiv. 2025 Nov 21. pii: 2025.11.20.689615. [Epub ahead of print]

Lipid droplets promote the aberrant liquid-liquid phase separation of alpha-synuclein leading to impaired energy homeostasis.

Jose Cevallos, Elena Eubanks, Sunghoo Jung, Yiming Huang, Elyse Guadagno, Neeharika Rao Suvvari, Aryan Doshi, Nitya Ravinutala, Alejandro Mosera, Nagendran Ramalingam, Arati Tripathi, Tim Bartels, Ulf Dettmer, Eleanna Kara.

Alpha-synuclein (αSyn) inclusions, termed Lewy bodies, are the characteristic neuropathological feature of Parkinson's disease. Growing evidence points towards a role of aberrant liquid-liquid phase separation in the dysregulation of αSyn and sequence of events that lead to the formation of Lewy bodies. However, the triggers leading to aberrant phase separation are unknown, as is the relevance of this phenomenon to the neurodegeneration process. In this study, we showed that αSyn spontaneously phase separates into condensates in the presence of lipid droplets. These lipid droplet-rich condensates represent a toxic species of αSyn that prevents the turnover of the entrapped lipid droplets; they are also toxic to neighbouring mitochondria which are depolarized and undergo increased mitophagy. These findings underscore the increasing importance of lipid droplets in the pathogenesis of neurodegenerative diseases, and Parkinson's disease in particular. The lipid droplets are significantly enriched within the neuromelanin in midbrain dopaminergic neurons in the substantia nigra and could therefore uniquely facilitate the early αSyn-associated neurodegeneration of this region in PD. Our findings reveal a novel pathway implicated in the dysregulation of αSyn that connects aberrant liquid-liquid phase separation, lipid droplets and mitochondrial toxicity.

DOI: https://doi.org/10.1101/2025.11.20.689615