bims-proned 2025-07-13 papers

bims-proned

Biomed News

on Proteostasis in neurodegeneration

Issue of 2025–07–13
twenty papers selected by
Verena Kohler, Umeå University

An aminosterol breaks the autocatalytic cycle of Aβ42 aggregation and protects cell membranes from its soluble aggregates.
Glial phagocytosis for synapse and toxic proteins in neurodegenerative diseases.
Tauopathies: Emerging discoveries on tau protein, with a special focus on Alzheimer's disease.
Biophysical and computational insights into glycol-mediated modulation of amyloid dye affinity.
Inhibitory mechanisms of amentoflavone on amyloid-β peptide aggregation revealed by replica exchange molecular dynamics.
TDP-43 Proteinopathies in ALS and FTLD: Mechanistic Insights and Therapeutic Approaches.
Mutant α-synuclein takes down autophagy.
Cordycepin promotes autophagic degradation of α-synuclein via CacyBP/SIP activation for ameliorating olfactory dysfunction against Parkinson's disease.
α-Synuclein-Assembled Synaptic Vesicle Pools at the Presynaptic Terminal: A Study of α-Synuclein Function Using a Novel Mouse Model.
α-Synuclein-Assembled Synaptic Vesicle Pools at the Presynaptic Terminal: A Study of α-Synuclein Function Using a Novel Mouse Model.
An Unstable ATG2A Variant Causes a Neurodegenerative Disorder via Impaired Autophagy and Proteotoxic Stress in Brain Atrophy.
The Fragile Balance: Autophagy's Role in Neurodegenerative Disease Progression.
Chameleonic Nature of Aβ: Implications for Alzheimer's and Other Amyloid Diseases.
Morphological inhibitors of aggregation-prone amyloid-β conformers: A computational exploration.
A novel stable transgenic zebrafish line expressing mCherry-tagged human alpha-synuclein in the nervous system and exhibiting all the key features of Lewy body disorders at larval stage.
Single-Domain Antibody-Based Autophagosome-Targeting Chimera for Tau Clearance and Motor Function Restoration in Tauopathies.
Chemical Targeting of the ATXN1 aa99-163 Interaction Site Suppresses polyQ-Expanded Protein Dimerization.
Cysteine string protein α and a link between rare and common neurodegenerative dementias.
Neurotoxicity of Endogenous Neurotoxin Salsolinol in Parkinson's Disease.
Autophagic stress activates distinct compensatory secretory pathways in neurons.

Proc Natl Acad Sci U S A. 2025 Jul 15. 122(28): e2417944122

An aminosterol breaks the autocatalytic cycle of Aβ42 aggregation and protects cell membranes from its soluble aggregates.

Lucas B Fallot, Johnathan R Pinc, Joseph E Buselmeier, Julia C Palchak, Supria S Shroff, Kaitlyn Zang, Dillon J Rinauro, Kate M Bacon, Michael Nguyen, Mary Claire Schleck, Alyssa R Cornell, Alexandra Oshidar, Donald J Darrell, Justus M Gabriel, Aidan K Wright, Liam R Sasser, Ryan P Kreiser, F John Burpo, Alessia Santambrogio, Peifeng Xu, Robert W Kubiak, Joseph Loverde, Victor A Jaffett, Justin R Toole, Denise Barbut, Michael Zasloff, Fabrizio Chiti, Alexander J Dear, Michele Vendruscolo, Ryan Limbocker.

  Aberrant aggregates of the 42-residue form of the amyloid-β peptide (Aβ42) are cytotoxic in Alzheimer's disease (AD). Cost-effective and chronically safe disease-modifying therapeutics are needed to address the AD medical emergency worldwide. To increase our understanding of the mechanisms of Aβ42-induced cytotoxicity and to investigate clinically relevant aminosterols, we study the impact of claramine on the aggregation kinetics and properties of Aβ42 aggregates, as well as the ability of these proteotoxic species to bind and disrupt cell membranes. Whereas previously studied aminosterols accelerated Aβ42 aggregation, we show that claramine potently inhibits Aβ42 amyloid fibril formation. We find that claramine stabilizes soluble Aβ42, speeding up primary and secondary nucleation into species with antiparallel β-sheet structure that are elongation incompetent, thereby depleting Aβ42 monomers from the aggregation reaction. This steroid-polyamine also dissociates Aβ42 fibrillar aggregates, resulting in the abrogation of the autocatalytic capacity of Aβ42 fibrils, and it also inhibits the aggregation of a tau fragment relevant to AD. Upon exposure of human neuroblastoma cells to stabilized Aβ42 oligomers, claramine effectively neutralized Aβ42 oligomer-induced cytotoxicity by preventing their binding to cell membranes. Owing to the unique mechanism of action of aminosterols to reduce the toxicity of soluble Aβ42 aggregates by protecting cell membranes, and the newly characterized ability of claramine to inhibit Aβ42 fibril formation and dissociate fibrillar Aβ42 resulting in the interruption of the positive feedback loop in Aβ42 aggregation, our findings further emphasize the relevance of this family of natural products as potential treatments for AD and other protein misfolding diseases.

Keywords:  Alzheimer’s; amyloid; chemical kinetics; drug discovery; protein misfolded oligomers

DOI:  https://doi.org/10.1073/pnas.2417944122
Mol Neurodegener. 2025 Jul 09. 20(1): 81

Glial phagocytosis for synapse and toxic proteins in neurodegenerative diseases.

Yeseong Choi, Won-Suk Chung.

Glia, as resident immune and supportive cells of the central nervous system, play a critical role in maintaining brain homeostasis. One of their key homeostatic functions is phagocytic capacity in pruning synapses and removing cellular debris/protein aggregates, a process vital for synaptic plasticity and brain maintenance. However, these phagocytic functions are often dysregulated with aging and in neurodegenerative diseases (NDs), such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and frontotemporal dementia. This review aims to examine the phagocytic roles of glia under both physiological and pathological conditions, with a special focus on their interactions with misfolded protein aggregates, including amyloid beta, tau, alpha synuclein, prion, huntingtin, and TAR DNA-binding protein 43. We also explore the fate of ingested molecules after being phagocytosed by glia-whether they are degraded, accumulate intracellularly, or are transferred between cells-and their implications for disease progression. Finally, we review current therapeutic strategies and the potential approaches for modulating glial phagocytosis to mitigate several NDs. We believe that understanding the exact mechanisms of glial phagocytosis and clearance will serve as key elements in developing future treatments for NDs.

DOI: https://doi.org/10.1186/s13024-025-00870-9
Neuropeptides. 2025 Jul 02. pii: S0143-4179(25)00036-8. [Epub ahead of print]112 102536

Tauopathies: Emerging discoveries on tau protein, with a special focus on Alzheimer's disease.

Aishwarya Hattiholi, Harsha Hegde, Suhas Kumar Shetty.

  Tauopathies encompass a group of neurodegenerative disorders (NDDs) driven by the abnormal accumulation of mutated tau protein, leading to hyperphosphorylation, neuronal damage, and neuroinflammation. The protein plays essential roles in brain function but undergoes hyperphosphorylation and aggregation into toxic oligomers in NDDs. Recent research emphasizes the need to understand tau's post-translational modifications (PTMs) and their role in pathological states. Insights into tau's structure, isoform-specific properties, and aggregation mechanisms are critical for elucidating its propagation in neurodegeneration. Moreover, tau's potential as a biomarker and the development of targeted therapies to mitigate tauopathies, particularly in AD, remain promising avenues. However, many strategies targeted at tau have repeatedly failed, which continues the search for better alternatives. This review focuses on recent advances in tau research, highlighting its structural and functional characteristics, and roles in disease, that may be critical to understanding their implications for new therapeutic strategies. PTMs are important for the stable structure and physiological functions of a protein. However, dysfunctional PTMs are the leading causes of tau protein aggregation. The recent shift on tau hyperphosphorylation has resulted in many discoveries related to their functions in AD. Therapeutic strategies targeting phosphorylated tau are being extensively studied worldwide. This paper gives a comprehensive view on these aspects.

Keywords:  Aggregation; Alzheimer's disease; Neurodegeneration; Post-translational modifications; Tau; Tauopathies

DOI:  https://doi.org/10.1016/j.npep.2025.102536
Int J Biol Macromol. 2025 Jul 07. pii: S0141-8130(25)06387-1. [Epub ahead of print] 145832

Biophysical and computational insights into glycol-mediated modulation of amyloid dye affinity.

Priyanka Mudad, Danish Alam, Bhanu Pratap Gurjar, Arun S Kharat, Asimul Islam.

Protein aggregation is main pathological hallmark of numerous neurodegenerative disorders. The characterization of protein aggregates is critical for understanding their role in disease progression as well as for developing therapeutic interventions. Thus, to study protein folding and aggregation, molecular crowding agents commonly being used to mimic the in vivo condition. Moreover, histological dyes such as Thioflavin T (ThT), 8-Anilino-1-naphthalenesulfonic acid (ANS), and Congo Red (CR) are prominent amyloid-sensitive dyes, each exhibiting distinct binding and fluorescence characteristics upon binding to amyloid fibrils. In this study, we investigated the effect of macromolecular crowding agents like Ethylene glycol (EG) and Polyethylene glycol (PEG) on binding and fluorescence properties of histological dyes. Various spectroscopic techniques revealed that there was increase and shift in the fluorescence of ThT and ANS with increasing concentration and molecular weight of PEGs and EG. Additionally, CR absorbance spectra showed structural changes in the dyes upon interaction with glycols. Further, microscopy showed altered morphology of dyes in the presence of these compounds. Moreover, molecular docking studies show that both PEGs and EG interact with the dye, thereby indicating that PEGs and EG potentially modulate the binding behavior of dyes to the protein aggregates. This study reveals that amyloid-sensitive dyes show non-specific binding with crowding agents, which can significantly impact the results when the protein is used for aggregation studies and lead to false positive results as well. Therefore, this study provides insight into interaction of dye with crowding agent, which suggests taking appropriate blanks for protein aggregation studies.

DOI: https://doi.org/10.1016/j.ijbiomac.2025.145832
Sci Rep. 2025 Jul 08. 15(1): 24352

Inhibitory mechanisms of amentoflavone on amyloid-β peptide aggregation revealed by replica exchange molecular dynamics.

Suxia Wu, Chang Liu, Yang Li, Xiaoyu Zhang, Qianji Han, Heng Zhao, Kun Zhao, Yaru Dang, Ruihan Wang, Shitao Song.

  Amyloid-β (Aβ) aggregation is a central pathological hallmark of Alzheimer's disease, with soluble trimers recognized as particularly neurotoxic species. Amentoflavone (AMF), a natural biflavonoid compound, has shown strong inhibitory effects on Aβ aggregation. However, its underlying molecular mechanism remains poorly understood. In this study, we employed replica exchange molecular dynamics (REMD) and molecular mechanics/Poisson-Boltzmann surface area (MM/PBSA) method to elucidate the interaction between AMF and Aβ peptides. Our results reveal that AMF preferentially binds to the 16KLVFFAEDV24 segment, a hydrophobic core that plays a critical role in the initiation of aggregation. It disrupts b-sheet formation through hydrophobic interactions with Leu-17, Phe-20, and Val-24. This binding stabilizes disordered coil conformations and prevents the conformational transitions required for fibril formation. Based on these findings, we performed structure-based virtual screening and identified two natural product-derived candidates with higher predicted affinity. These insights provide an atomic-level understanding of AMF's inhibitory mechanism and support the rational design of natural product-inspired inhibitors that target Aβ aggregation.

Keywords:  Aggregation Inhibition mechanism; Amentoflavone; Amyloid-β aggregation; Molecular dynamics simulation; Virtual screening

DOI:  https://doi.org/10.1038/s41598-025-10623-9
CNS Neurol Disord Drug Targets. 2025 Jul 03.

TDP-43 Proteinopathies in ALS and FTLD: Mechanistic Insights and Therapeutic Approaches.

Shilpi Chauhan, Preeti Maan, Archna Panghal.

  TAR DNA-binding protein 43 (TDP-43) is a vital RNA/DNA-binding protein involved in RNA metabolism, playing a key role in the pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Approximately 97% of sporadic ALS (sALS), familial ALS (fALS) and FTLD cases are associated with pathological inclusions of hyperphosphorylated and ubiquitinated TDP-43 and genetic mutations in TAR DNA binding protein (TARDBP). Besides TARDBP, mutations in other genes such as C9ORF72, SOD1, FUS, and NEK1 are also linked to other fALS cases. Cytoplasmic mislocalization, aberrant post-translational modifications, and amyloid- like aggregation characterize TDP-43 pathology. These pathological changes impair essential cellular processes, including gene expression, mRNA stability, and RNA metabolism. Mechanisms of TDP-43-induced toxicity include disruption of endocytosis, mitochondrial dysfunction, and progressive cellular damage. Additionally, liquid-liquid phase separation (LLPS) and prion-like propagation are emerging as central features of its pathological spread. This review summarizes advances in understanding TDP-43's physiological functions and pathological mechanisms in ALS and FTLD. It highlights key processes underlying TDP-43 toxicity, such as aggregation, selective neuronal vulnerability, and regional susceptibility. Finally, this review summarizes evolving therapeutic strategies aimed at mitigating TDP-43-related toxicity through disaggregation, targeting mislocalization, and addressing upstream dysfunctions and challenges faced in the development of effective therapies for ALS and FTLD.

Keywords:  TDP-43; TDP-43 toxicity.; amyotrophic lateral sclerosis; dementia; frontotemporal lobar degeneration; proteinopathy

DOI:  https://doi.org/10.2174/0118715273374466250617085832
Sci Signal. 2025 Jul 08. 18(894): eaea2255

Mutant α-synuclein takes down autophagy.

Leslie K Ferrarelli.

Parkinson's disease-associated α-synuclein impairs autophagy by hijacking the cell's acetylation machinery.

DOI: https://doi.org/10.1126/scisignal.aea2255
Free Radic Biol Med. 2025 Jul 08. pii: S0891-5849(25)00814-7. [Epub ahead of print]

Cordycepin promotes autophagic degradation of α-synuclein via CacyBP/SIP activation for ameliorating olfactory dysfunction against Parkinson's disease.

Ying-Ying Gu, Ming-Xuan Liu, Xin-Ru Zhao, Ying Yi, Jia-Yi Wang, Yi-Lin Lin, Xiao-le Xu, Xiao-Ling Zhang.

  Olfactory dysfunction is one of the earliest non-motor symptoms of Parkinson's disease (PD), accompanied by abnormal α-synuclein aggregation in the olfactory bulb (OB). We previously reported that Cordycepin (Cor), a potential anti-inflammatory and anti-oxidative adenosine derivative, has emerged as an attractive candidate for PD treatment. However, existing investigations have predominantly focused on the amelioration of motor symptoms rather than modulating the disease course from prodromal stage. This study aimed to evaluate if Cor exerts a disease-modifying effect at the prodromal stage prior to the onset of motor deficits in eight-week-old male C57BL/6 mice exposed to rotenone. Our results showed that Cor administration significantly attenuated olfactory dysfunction and delayed the onset of motor impairments. This therapeutic effect was concomitant with pathological α-synuclein aggregates degradation in OB. RNA sequencing analyses revealed that Autophagy-lysosomal pathway (ALP) in OB may be associated with the neuroprotective actions of Cor in PD. Furthermore, Cor significantly stabilized Calcyclin-binding protein/Siah1-interacting protein (CacyBP/SIP) via inhibiting its ubiquitin-proteasome degradation in rotenone-treated SH-SY5Y cells. This stabilization suppressed NLRP3 inflammasome activation and subsequently enhanced autophagosome-lysosome fusion, culminating in the autophagic degradation of α-synuclein. Notably, blockade of CacyBP/SIP abrogated the neuroprotective effects of Cor against rotenone-induced olfactory impairment. Collectively, these findings suggest CacyBP/SIP-NLRP3-α-synuclein axis may serve as a key target of Cor in the early treatment of PD, which provides novel insights into the mechanisms for the anti-PD effect of Cor.

Keywords:  CacyBP/SIP; Olfactory dysfunction; Parkinson disease; autophagy flux; α-synuclein

DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.07.010
Acta Histochem Cytochem. 2025 Jun 24. 58(3): 107-114

α-Synuclein-Assembled Synaptic Vesicle Pools at the Presynaptic Terminal: A Study of α-Synuclein Function Using a Novel Mouse Model.

Chigure Suzuki, Junji Yamaguchi, Isei Tanida, Yasuo Uchiyama.

  α-Synuclein is the causative gene for PARK1 and PARK4 (heterozygous triplication of SNCA) and is associated with Parkinson's disease, where it localizes to presynaptic terminals in mature neurons. Beyond Parkinson's disease, α-synuclein has also been implicated in various other neuronal disorders. In vitro studies using purified α-synuclein protein have suggested it is involved in synaptic vesicle assembly. However, its physiological function and the ultrastructure of its localization sites in presynaptic terminals remain unclear. To address this, we generated transgenic mice overexpressing human α-synuclein tagged with mKate2 (hSNCA-mKate2 mice) to investigate its in vivo role in synaptic vesicle pool formation at presynaptic terminals. These mice showed normal growth and fertility, and even at 1-yr. old, they showed no motor dysfunction compared to their wild-type littermates. Additionally, no abnormal protein aggregates indicative of neurodegeneration were observed. In this review, we summarize recent findings on the in vivo role of α-synuclein within presynaptic terminals, utilizing hSNCA-mKate2 mice in combination with in-resin correlative light and electron microscopy, electron microscopy, and immunohistochemistry.

Keywords:  in-resin CLEM; mKate2; synaptic vesicle pool; transgenic mouse; α-synuclein

DOI:  https://doi.org/10.1267/ahc.25-00017
Acta Histochem Cytochem. 2025 Jun 24. 58(3): 107-114

α-Synuclein-Assembled Synaptic Vesicle Pools at the Presynaptic Terminal: A Study of α-Synuclein Function Using a Novel Mouse Model.

Chigure Suzuki, Junji Yamaguchi, Isei Tanida, Yasuo Uchiyama.

  α-Synuclein is the causative gene for PARK1 and PARK4 (heterozygous triplication of SNCA) and is associated with Parkinson's disease, where it localizes to presynaptic terminals in mature neurons. Beyond Parkinson's disease, α-synuclein has also been implicated in various other neuronal disorders. In vitro studies using purified α-synuclein protein have suggested it is involved in synaptic vesicle assembly. However, its physiological function and the ultrastructure of its localization sites in presynaptic terminals remain unclear. To address this, we generated transgenic mice overexpressing human α-synuclein tagged with mKate2 (hSNCA-mKate2 mice) to investigate its in vivo role in synaptic vesicle pool formation at presynaptic terminals. These mice showed normal growth and fertility, and even at 1-yr. old, they showed no motor dysfunction compared to their wild-type littermates. Additionally, no abnormal protein aggregates indicative of neurodegeneration were observed. In this review, we summarize recent findings on the in vivo role of α-synuclein within presynaptic terminals, utilizing hSNCA-mKate2 mice in combination with in-resin correlative light and electron microscopy, electron microscopy, and immunohistochemistry.

Keywords:  in-resin CLEM; mKate2; synaptic vesicle pool; transgenic mouse; α-synuclein

DOI:  https://doi.org/10.1267/ahc.25-00017
Clin Genet. 2025 Jul 09.

An Unstable ATG2A Variant Causes a Neurodegenerative Disorder via Impaired Autophagy and Proteotoxic Stress in Brain Atrophy.

S Rehan Ahmad, Md Zeyaullah, Abdullah M AlShahrani, Danish Qavi, Abdelrhman A G Altijani, Mohammad Suhail Khan, Khursheed Muzammil.

  Autophagy is a critical cellular process for maintaining proteostasis and neuronal health. Disruption of this pathway is increasingly recognized in pediatric neurodegenerative disorders. Here, we study a novel previously uncharacterized homozygous and autosomal recessive missense variant, c.1372G>C (p.Gly433Ala), in the autophagy gene ATG2A, identified in a 3-year-old female proband presenting with developmental regression, seizures, cerebellar ataxia, and MRI-confirmed diffuse cerebral and cerebellar atrophy. The affected residue, Gly433, is evolutionarily conserved across eukaryotes and predicted to be structurally and functionally critical. Computational modeling and molecular dynamics simulations revealed that the G433A substitution induces local β-sheet extension, increased protein flexibility, higher aggregation propensity, and global structural destabilization. Proband-derived fibroblasts expressing ATG2A-G433A showed normal transcript and protein levels, but exhibited mislocalization of ATG2A to the cytosol, reduced colocalization with LC3B, loss of autophagosome formation, and a marked increase in protein aggregates. Proteotoxic stress was further evidenced by significant accumulation of Proteostat- and SQSTM1-positive granules. Additionally, transcript levels of unfolded protein response markers (GRP78, PERK, ATF4, and CHOP) were significantly upregulated, suggesting increased ER stress signaling. Cell cycle analysis revealed a substantial increase in cell death in proband fibroblasts. Overall, our findings identify ATG2A as a potentially novel disease gene and its G433A variant as a pathogenic substitution that disrupts autophagy and proteostasis, driving neurodegeneration via aggregation-prone misfolding and autophagy failure. This work depicts the first clinical spectrum of ATG2A-related neurodegenerative disorders and highlights the importance of autophagy maintenance in pediatric neurodevelopmental processes.

Keywords:  ATG2A; autophagy; neurodegeneration; pediatric seizure; protein aggregation

DOI:  https://doi.org/10.1111/cge.70019
Curr Neuropharmacol. 2025 Jul 03.

The Fragile Balance: Autophagy's Role in Neurodegenerative Disease Progression.

Bharat Bhushan, Meenakshi Dhanawat, Garima, Kashish Wilson, Sumeet Gupta, Samrat Chauhan.

  Autophagy relates to the mechanism underlying the intracellular constituents' breakdown by lysosomes. Autophagy plays an essential role in preserving and regulating cellular homeostasis by mediating the degradation of intracellular components and recycling their decomposition products. It was demonstrated that autophagy operates in-vivo in the starving reaction, initial growth, internal control of quality, and cell division. Autophagy malfunction is perhaps connected with cancer and neurological conditions, as demonstrated by current research. In conjunction with the identification of specific mutations associated with autophagy-related disorders and deeper knowledge of the pathophysiology of disorders caused by aberrant disintegration of particular autophagy substrates, autophagy activation serves a vital part in prolonging lifespans and suppressing the process of aging. To safeguard the homeostasis within a cell, cells have developed sophisticated quality-control procedures for organelles and proteins. These quality-control mechanisms maintain cellular integrity through degradation by the autophagy-lysosome or ubiquitin-proteasome systems, as well as through protein folding assistance (or refolding of misfolded proteins) provided by molecular chaperones. A great deal of neurodegenerative illnesses are indicated by the development of intracellular inclusions formed from misfolded proteins, which are believed to be an outcome of defective autophagy. Additionally, it was recently discovered that neurodegenerative illnesses are also linked with mutations in key autophagy-related genes. However, pathogenic proteins like α-synuclein and amyloid β cause damage to the autophagy system. This paper examines the recent advancements in our understanding of the link between autophagic abnormalities and the development of neurological disorders, and proposes that activating autophagy could serve as a potential therapeutic strategy.

Keywords:  Autophagy; autophagy-related gene; cancer; heart disease; liver disease; neurodegenerative disease.; protein aggregates

DOI:  https://doi.org/10.2174/011570159X377552250627113915
Bioessays. 2025 Jul 11. e70039

Chameleonic Nature of Aβ: Implications for Alzheimer's and Other Amyloid Diseases.

Birgit Strodel.

  The amyloid-β peptide (Aβ), implicated in Alzheimer's disease, exhibits significant polymorphism. At the monomer level, Aβ can adopt disordered, helical, and β-hairpin structures, influenced by environmental conditions. Both oligomeric and fibrillar states, characterized by the prevalence of β-sheets, are polymorphic in the arrangement of β-strands. This chameleon-like behavior arises from Aβ's unique sequence and relatively flat energy landscape, which facilitates aggregation and may contribute to the prevalence of Alzheimer's disease, while also enabling disaggregation, thus slowing disease progression. In contrast, Creutzfeldt-Jakob disease, which is much rarer, progresses far more rapidly, likely due to the steeper energy landscape of the prion protein.

Keywords:  Alzheimer's disease; amyloid aggregation; conformational energy landscape; energy landscape–amyloid disease relationship; polymorphism

DOI:  https://doi.org/10.1002/bies.70039
Comput Biol Med. 2025 Jul 04. pii: S0010-4825(25)00896-0. [Epub ahead of print]196(Pt A): 110545

Morphological inhibitors of aggregation-prone amyloid-β conformers: A computational exploration.

Stefano Bosio, Federico Falchi, Chiara Rauzi, Luca Bellucci.

  Alzheimer's disease is a neurodegenerative disorder characterized by progressive cognitive decline and memory loss. It is associated with the self-assembly of the amyloid-β peptide, a soluble intrinsically disordered protein naturally present in the brain parenchyma in various alloforms. This study presents a computational approach to identify possible modulators of the monomeric aggregation-prone conformations of amyloid-β, a critical intermediate in the fibrillation process. A structure-based virtual screening campaign was designed using a structural ensemble to identify potential binders. The workflow included binding site identification, small molecule-peptide docking, protein-protein docking, and molecular dynamics simulations to evaluate interaction stability and aggregation propensity. From this pipeline, a set of novel molecules was identified as capable of interacting with aggregation-prone forms of amyloid-β, potentially reducing their tendency to form toxic aggregates.

Keywords:  Aggregation inhibitors; Alzheimer’s disease; Amyloid-β; Amyloid-β aggregation; Intrinsically disordered proteins; Molecular dynamics

DOI:  https://doi.org/10.1016/j.compbiomed.2025.110545
Neurobiol Dis. 2025 Jul 05. pii: S0969-9961(25)00234-7. [Epub ahead of print]213 107018

A novel stable transgenic zebrafish line expressing mCherry-tagged human alpha-synuclein in the nervous system and exhibiting all the key features of Lewy body disorders at larval stage.

Silvia Zini, Alessia Muscò, Francesca Longhena, Gaia Faustini, Chiara Tobia, Giuseppe Borsani, Maria Grazia Spillantini, Daniela Zizioli, Arianna Bellucci.

  Lewy Bodies, proteinaceous inclusions containing α-Synuclein fibrillary aggregates, are defining neuropathological hallmarks of Parkinson's disease and Dementia with Lewy Bodies. Recently, zebrafish arose as a valuable model to study neurodegenerative diseases, but despite attempts to generate stable human α-Synuclein transgenic zebrafish lines recapitulating the main phenotypic characteristics of Lewy Body disorders, i.e., α-Synuclein fibrillary aggregate deposition, neurodegeneration and behavioral deficits, none of the models produced so far could develop all these features. Here, we describe the generation of a novel transgenic zebrafish line stably expressing human α-Synuclein in the nervous system and developing all the key Parkinson's Disease phenotypic traits during larval stage, named Tg(elavl3:mCherry-hsa.SNCA). By behavioral studies, molecular biology analysis, confocal and light-sheet fluorescence microscopy we found that Tg(elavl3:mCherry-hsa.SNCA) larvae developed basal motility deficits and anxiety traits as well as a significant increase of brain apoptotic cells in parallel with marked reduction of tyrosine hydroxylase-immunopositivity in forebrain regions at 5 days post fertilization. The Tg(elavl3:mCherry-hsa.SNCA) larvae accumulated Thioflavin-S-positive and high molecular weight serine-129-phosphorylated α-Synuclein. Furthermore, they displayed other typical pathologic alterations associated with Parkinson's Disease and Dementia with Lewy Bodies, such as accumulation of synapsins and changes in key autophagy markers. These findings, coupled with the suitability of larval zebrafish for high-throughput screening, support that the novel Tg(elavl3:mCherry-hsa.SNCA) line constitutes the first stable zebrafish experimental model for rapid and reliable studies addressing both the molecular basis of Lewy body disorders and the efficacy of new therapeutic approaches.

Keywords:  Behavioral abnormalities; Neurodegeneration; Parkinson's disease; Zebrafish; Α-Synuclein

DOI:  https://doi.org/10.1016/j.nbd.2025.107018
bioRxiv. 2025 Jul 04. pii: 2025.06.30.662446. [Epub ahead of print]

Single-Domain Antibody-Based Autophagosome-Targeting Chimera for Tau Clearance and Motor Function Restoration in Tauopathies.

Yixiang Jiang, Amber M Tetlow, Yan Lin, Changyi Ji, Klaudia F Laborc, Adam C Mar, Ruimin Pan, Xiang-Peng Kong, Erin E Congdon, Einar M Sigurdsson.

Tauopathies are neurodegenerative diseases characterized by pathological tau accumulation, leading to motor and neuropsychiatric symptoms. Effective tau-targeting therapies remain a major challenge. Here, we present 1D9-LIRΔTP53INP2, a single-domain antibody (sdAb)-based protein degrader that facilitates tau clearance via the autophagy-lysosomal pathway. This engineered molecule combines the anti-tau sdAb 1D9 with an LC3-interacting region (LIRΔTP53INP2) to promote autophagosomal recruitment, mimicking autophagy receptors by simultaneously binding tau and LC3. In frontotemporal dementia (FTD) patient-derived neurons and JNPL3 tauopathy mice, both harboring the P301L tau mutation, 1D9-LIRΔTP53INP2 significantly reduced tau levels and improved motor function in mice. These findings underscore the therapeutic potential of sdAb-based protein degraders for tauopathies. Given the challenges of brain delivery for conventional antibodies, sdAbs with enhanced brain penetration and efficacy offer a promising strategy for treatment of neurodegenerative diseases.

DOI: https://doi.org/10.1101/2025.06.30.662446
ACS Omega. 2025 Jul 01. 10(25): 27194-27205

Chemical Targeting of the ATXN1 aa99-163 Interaction Site Suppresses polyQ-Expanded Protein Dimerization.

Ioannis Gkekas, Katerina Pliatsika, Stelios Mylonas, Sotirios Katsamakas, Apostolos Axenopoulos, Simona Kostova, Erich E Wanker, Dimitra Hadjipavlou-Litina, Konstantinos Xanthopoulos, Petros Daras, Spyros Petrakis.

Spinocerebellar ataxia type 1 (SCA1) is a neurodegenerative disease caused by the expansion of a polyglutamine (polyQ) tract in the ATXN1 protein. This expansion is thought to be responsible for the gradual aggregation of the mutant protein, which is associated with increased cytotoxicity and neuronal cell death. Apart from the polyQ tract, other domains in ATXN1 are also involved in the initial events of protein aggregation, such as a dimerization domain that promotes protein oligomerization. ATXN1 interacts with various proteins; among them, MED15 significantly enhances the aggregation of the polyQ-expanded protein. Therefore, we set to identify the interaction site between ATXN1 and MED15 and assess whether its chemical targeting would affect polyQ protein aggregation. First, we predicted the structures of ATXN1 and MED15 and simulated their interaction. We experimentally validated that amino acids (aa) 99-163 of ATXN1 and aa548-665 of MED15 are critical for this protein-protein interaction (PPI). We also showed that the aa99-163 domain in ATXN1 is involved in the dimerization of the mutant isoform. Targeting this domain with a chemical compound identified through virtual screening (Chembridge ID: 5755483) inhibited both the interaction of ATXN1 with MED15 and the dimerization of polyQ-expanded ATXN1. These results strengthen our assumption that the aa99-163 domain of ATXN1 may be involved in polyQ protein aggregation and highlight compound 5755483 as a potent first-in-class therapeutic agent for SCA1.

DOI: https://doi.org/10.1021/acsomega.5c02465
NPJ Dement. 2025 ;1(1): 15

Cysteine string protein α and a link between rare and common neurodegenerative dementias.

Matthew J Rosene, Bruno A Benitez.

  The maintenance of protein homeostasis and overall protein quality control dysfunction are associated with dementia. Cysteine string protein α (CSPα) is an endolysosomal cochaperone that facilitates the fusion of secretory and synaptic vesicles to the cell membrane. CSPα interacts with multiple proteins related to the proteostasis network and exocytic pathways and is often dysfunctional in synaptopathies. Since the initial discovery of CSPα 30 years ago, subsequent research has demonstrated a protective role of CSPα, especially in synaptic maintenance. However, the discovery of heterozygous CSPα mutations in 2011 causing adult-onset neuronal ceroid lipofuscinosis (ANCL) shifted the back-then prevalent dogma of unique synaptic function to include an endolysosomal role for CSPα. Recently, CSPα has been involved in the exocytosis of aggregate-prone proteins through either the misfolding-associated protein secretion (MAPS) or unconventional secretory pathways linking the molecular mechanism of rare and common neurodegenerative diseases. Here, we propose a novel molecular and pathophysiological model of CSPα-associated dementia, outline the increasing evidence of a broader role of CSPα in neurodegeneration, propose the role of CSPα in the synaptic secretion of neurodegenerative-associated proteins, and discuss the modulation of CSPα as a molecular target for common dementias.

Keywords:  Alzheimer's disease; Amyotrophic lateral sclerosis; Cellular neuroscience; Dementia; Molecular neuroscience; Motor neuron disease; Neurodegeneration; Parkinson's disease

DOI:  https://doi.org/10.1038/s44400-025-00016-0
CNS Neurol Disord Drug Targets. 2025 Jul 09.

Neurotoxicity of Endogenous Neurotoxin Salsolinol in Parkinson's Disease.

Shuang Wu, Yu'an Zhou, Qiang Li, Huiyan Sun, Lida Du, Hongquan Wang.

  Salsolinol (SAL), an endogenous neurotoxin 1-methyl-6,7-dihydroxy-1,2,3,4- tetrahydroisoquinoline, is a dopamine metabolite that has been implicated in the pathogenesis of Parkinson's disease (PD) due to its selective toxicity toward dopaminergic (DA) neurons. Experimental studies have demonstrated that SAL induces DA neuronal injury both in vitro and in vivo, thereby contributing to the PD pathogenesis. Given its specificity for nigral DA neurons, SAL serves as a more relevant model for studying PD-associated brain waste clearance and neurotoxicity, as it recapitulates the progressive nature of the disease. Emerging evidence indicates that SAL exerts its neurotoxic effects primarily through the induction of oxidative stress and regulated cell death in DA neurons. With the escalating global burden of PD and unmet need for therapies targeting multifactorial mechanisms, the dual role of SAL as both a dopamine derivative and mediator of protein aggregation links metabolic dysfunction to neurodegeneration, positioning it as a pivotal target for understanding sporadic PD and therapeutic development. In this review, we summarize current knowledge on the molecular mechanisms underlying SAL-induced neurotoxicity and its pathophysiological role in PD. By elucidating these mechanisms, this review provides valuable insights for future research in uncovering underestimated molecular targets for therapeutic intervention in PD.

Keywords:  Parkinson’s disease; ferroptosis; neurotoxicity; regulated cell death.; salsolinol

DOI:  https://doi.org/10.2174/0118715273379940250704062355
Proc Natl Acad Sci U S A. 2025 Jul 15. 122(28): e2421886122

Autophagic stress activates distinct compensatory secretory pathways in neurons.

Sierra D Palumbos, Jacob Popolow, Juliet Goldsmith, Erika L F Holzbaur.

  Autophagic dysfunction is a hallmark of neurodegenerative disease, leaving neurons vulnerable to the accumulation of damaged organelles and aggregated proteins. However, the late onset of diseases suggests that compensatory quality control mechanisms may be engaged to delay these deleterious effects. Neurons expressing common familial Parkinson's disease-associated mutations in the leucine-rich repeat kinase 2 (LRRK2) exhibit defective autophagy. Here, we demonstrate that both primary murine neurons and human induced Pluripotent Stem Cells (iPSC)-derived neurons harboring pathogenic LRRK2 upregulate the secretion of extracellular vesicles. We used unbiased proteomics to characterize the secretome of LRRK2G2019S neurons and found that autophagic cargos including mitochondrial proteins were enriched. Based on these observations, we hypothesize that autophagosomes are rerouted toward secretion when cell-autonomous degradation is compromised to mediate clearance of undegraded cellular waste. Immunoblotting confirmed the release of autophagic cargos and live-cell imaging demonstrated that secretory autophagy is upregulated in LRRK2G2019S neurons. We also found that LRRK2G2019S neurons upregulate the release of exosomes containing microRNAs. Live-cell imaging confirmed that this upregulation of exosomal release is dependent on hyperactive LRRK2 activity, while pharmacological experiments indicate that this release staves off apoptosis. Finally, we show that markers of both vesicle populations are upregulated in plasma from mice expressing pathogenic LRRK2. In sum, we find that neurons expressing pathogenic LRRK2 upregulate secretory autophagy and the compensatory release of exosomes to mediate waste disposal and transcellular communication, respectively. We propose that this increased secretion contributes to the maintenance of cellular homeostasis, delaying neurodegenerative disease progression over the short term while potentially contributing to neuroinflammation over the longer term.

Keywords:  Parkinson’s disease; autophagy; neurodegeneration; secretion

DOI:  https://doi.org/10.1073/pnas.2421886122