bims-proned 2026-06-07 papers

bims-proned

Biomed News

on Proteostasis in neurodegeneration

Issue of 2026–06–07
nine papers selected by
Verena Kohler, Umeå University

A Conjugate of Aminoadamantane and Tetrahydro-γ-Carboline Inhibits Accumulation of Mutant α-Synuclein A53T in the Cellular Model of Proteinopathy.
Therapeutic Peptide SS-31 Modulates Membrane Binding and Aggregation of α-Synuclein and Restores Impaired Mitochondrial Function.
A Rigid Supramolecular Solution to a Flexible Problem: A Multifunctional Calix[4]arene-Based Strategy to Prevent α‑Synuclein Toxicity.
Remediating Biotoxicity with Synthetic Receptors.
Phytochemical engineered quantum dots as potential therapy to counter alpha synuclein aggregation in Parkinson's disease.
Glypican-1: a modulator of neurodegenerative and tumorigenic pathways.
Ribonucleic acid as an active driver of protein aggregation in neurodegeneration.
The vicious cycle: unraveling the interplay between α-synuclein, mitochondrial dysfunction, and neuroinflammation in Parkinson's disease.
Lipid Dynamics in the Amyloid Cascade Hypothesis: Evaluating the Biological Relevance of In Vitro Models.

Biochemistry (Mosc). 2026 May;91(5): 789-799

A Conjugate of Aminoadamantane and Tetrahydro-γ-Carboline Inhibits Accumulation of Mutant α-Synuclein A53T in the Cellular Model of Proteinopathy.

Marina V Burak, Nadezhda E Pukaeva, Victoria S Kryshkova, Olga A Kukharskaya, Maya R Nazdracheva, Sergey A Pukhov, Kirill A Rachenkov, Alla V Stavrovskaya, Vladimir P Fisenko, Michail S Kukharsky, Sergei O Bachurin.

  Pathological aggregation of α-synuclein is a key event in the development of synucleinopathies, such as Parkinson's disease and Lewy body dementia. Currently, no effective disease-modifying therapy is available, necessitating the search for new therapeutic agents. One promising strategy involves the use of low-molecular-weight compounds capable of inhibiting the formation of toxic protein aggregates. This study evaluates the anti-aggregation properties of EC3222x, a conjugate of pharmacophoric fragments of amantadine and a fluorinated derivative of tetrahydro-γ-carboline. α-Synucleinopathy was modeled in the SH-SY5Y neuroblastoma cell line by transfection with a plasmid vector encoding the mutant human α-synuclein A53T protein. EC3222x at a concentration of 1 µM reduced the number of cells with α-synuclein A53T aggregates. Its efficacy was comparable to that of SynuClean-D and Buntanetap, known inhibitors of α-synuclein aggregation. Treatment with EC3222x reduced both the level of diffusely distributed intracellular α-synuclein and the formation of mature fibrillar aggregates and large aggresomes. Importantly, EC3222x did not affect the accumulation of another aggregation-prone protein, TDP-43, in a similar cellular model, indicating its specificity for α-synuclein. These findings suggest that EC3222x may represent a promising candidate for the development of therapeutic agents targeting synucleinopathies.

Keywords:  cellular models; neurodegenerative diseases; neuroprotective agents; protein aggregation; protein aggregation inhibitors; α-synuclein

DOI:  https://doi.org/10.1134/S0006297926600079
Chem Biol Drug Des. 2026 Jun;107(6): e70332

Therapeutic Peptide SS-31 Modulates Membrane Binding and Aggregation of α-Synuclein and Restores Impaired Mitochondrial Function.

Ewelina Stefaniak, Beiyuan Cui, Xucheng Yan, Kexin Sun, Xiangyu Teng, Liming Ying.

  Membrane binding and aggregation properties of α-synuclein are closely associated with Parkinson's disease and a class of related syndromes named as synucleinopathy. This study explored the potential of SS-31 (Elamipretide), a therapeutic tetrapeptide with alternating cationic and aromatic residues and known properties of mitochondrial inner membrane binding and oxidative stress reduction, in modulating α-synuclein interaction with the lipid membranes and mitigating the impairment of mitochondrial function induced by α-synuclein oligomers. It was demonstrated by both fluorescence correlation spectroscopy and fluorescence anisotropy that SS-31 displaces both wild-type and N-terminal acetylated α-synuclein from negatively charged small unilamellar vesicles in a dose-dependent manner. Thioflavin-T assay and transmission electron microscopy showed that SS-31 inhibits membrane-induced α-synuclein aggregation and alters the morphology of α-synuclein fibrils. Moreover, MTT assay and Seahorse Mito Stress Test indicated that SS-31 enhances cell viability and restores impaired mitochondrial function in α-synuclein oligomer-treated neuroblastoma cells. Finally, confocal imaging revealed that SS-31 hinders cellular uptake of α-synuclein oligomers, possibly by modifying cell membrane electrostatics. These findings suggest that SS-31 potentially attenuates α-synuclein induced mitochondrial impairment via its interaction with the lipid membranes, justifying further development of a peptide-based intervention against α-synuclein mediated pathology.

Keywords:  SS‐31 peptide; lipid membrane; mitochondrial function; α‐Synuclein

DOI:  https://doi.org/10.1111/cbdd.70332
ACS Cent Sci. 2026 May 27. 12(5): 669-683

A Rigid Supramolecular Solution to a Flexible Problem: A Multifunctional Calix[4]arene-Based Strategy to Prevent α‑Synuclein Toxicity.

Davide Dell'Accantera, Giulia Piccinini, Cristina Ciabini, Isabella C Felli, Stefano Volpi, Nelson Marmiroli, Francesco Sansone, Roberta Ruotolo.

The pathological aggregation of α-synuclein (syn) is a hallmark of Parkinson's disease (PD) and related synucleinopathies. In the present study, we report a supramolecular strategy to reduce syn aggregation and its associated cellular toxicity using a panel of rationally designed anionic calix[4]-arenes. Among them, CLXP1, a tetraphosphonato derivative with a rigid, preorganized cavity, emerged as a potent inhibitor of syn aggregation in a validated yeast model of PD based on syn overexpression. CLXP1 significantly improved cell viability by reducing the formation of toxic intracellular inclusions of syn and restoring multiple dysregulated molecular pathways while preserving mitochondrial morphology and redox and lipid homeostasis and enhancing autophagic clearance. NMR analyses revealed that CLXP1 interacts with key residues of the N-terminal domain of syn, critically involved in membrane anchoring and oligomerization, supporting a model in which this interaction stabilizes the α-helical, membrane-bound conformation of syn, thereby preventing its progression toward toxic oligomeric species. These findings highlight the potential of supramolecular host-guest chemistry to selectively target intrinsically disordered proteins and provide a promising scaffold for the development of new modulators of protein aggregation.

DOI: https://doi.org/10.1021/acscentsci.5c02416
ACS Cent Sci. 2026 May 27. 12(5): 559-561

Remediating Biotoxicity with Synthetic Receptors.

Richard J Hooley.

Water-soluble synthetic receptors selectively bind α-synuclein in cells and disrupt the formation of prion-like aggregates, remediating the toxic effects of aggregation.

DOI: https://doi.org/10.1021/acscentsci.6c00706
Neurochem Int. 2026 Jun 02. pii: S0197-0186(26)00085-9. [Epub ahead of print]198 106194

Phytochemical engineered quantum dots as potential therapy to counter alpha synuclein aggregation in Parkinson's disease.

Priya Shashwat, Arivarsan Vishnu Kirthi, Manickam Selvaraj, Arun Karnwal, Joydeep Dutta.

  Parkinson's disease (PD) is a prevalent neurodegenerative disorder that critically impairs human health and presently lacks effective cellular-level therapeutic interventions. The disease is primarily characterized by pathological aggregation of misfolded α-synuclein in presynaptic neurons, leading to dopaminergic neuronal loss. The limited efficacy of current pharmacological treatments stems largely from challenges in crossing the blood-brain barrier. Recent studies suggest that nano-phytomedicine approaches offer promising alternatives for PD management. Specifically, phytochemical-engineered carbon quantum dots (CQDs) show potential to modulate key pathological processes, including α-synuclein aggregation, mitochondrial dysfunction, oxidative stress, and neuronal degeneration. Evidence from related neurodegenerative models, such as Alzheimer's disease, reveals that multifunctional CQDs can scavenge reactive oxygen species, influence protein aggregation, and mitigate neurotoxicity. The synergistic integration of bioactive phytochemicals into CQDs could enhance drug bioavailability, pharmacokinetic properties, and cellular repair mechanisms while reducing toxicity. This review discusses the design strategies, therapeutic mechanisms, and biological interactions of phytochemical-engineered CQDs, emphasizing their potential as next-generation nanocarriers and intrinsic neurotherapeutic agents for PD treatment.

Keywords:  Aggregated α-synuclein; Bioactive phytochemicals; Carbon quantum dots; Parkinson's disease; Pharmacokinetic properties; SNPC

DOI:  https://doi.org/10.1016/j.neuint.2026.106194
Front Neurosci. 2026 ;20 1850145

Glypican-1: a modulator of neurodegenerative and tumorigenic pathways.

Katrin Mani.



Keywords:  Alzheimer's disease; Parkinson's disease; ascorbate; glypican-1; heparan sulfate; neurodegeneration; nitric oxide; proteostasis

DOI:  https://doi.org/10.3389/fnins.2026.1850145
Curr Opin Struct Biol. 2026 Jun 05. pii: S0959-440X(26)00080-1. [Epub ahead of print]99 103298

Ribonucleic acid as an active driver of protein aggregation in neurodegeneration.

Francesco A Aprile, Annalisa Pastore.

Neurodegeneration has traditionally been largely attributed to protein aggregation, yet ribonucleic acid (RNA) has emerged as an active driver of pathology. Expanded repeat RNAs, misregulated RNA-binding proteins, and aberrant RNA-protein interactions can directly or indirectly trigger neuronal dysfunction, although the distinction between the two mechanisms might, in some cases, be loose. RNA modulates prion-like aggregation, scaffolds liquid-liquid phase separation, and either promotes or inhibits protein assembly, depending on RNA sequence and structure. The aim of this review is to discuss our current understanding of RNA's dual role-as a facilitator of aggregation or as a potential therapeutic target-revealing new mechanistic insights into diseases such as amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and spinocerebellar ataxias. We highlight RNA metabolism as a central determinant of neuronal vulnerability.

DOI: https://doi.org/10.1016/j.sbi.2026.103298
J Neurol. 2026 May 30. pii: 350. [Epub ahead of print]273(6):

The vicious cycle: unraveling the interplay between α-synuclein, mitochondrial dysfunction, and neuroinflammation in Parkinson's disease.

Yu-Lin Liang, Feng-Ge Yang, Qiang Tang.

  Parkinson's disease (PD) is the second most common neurodegenerative disorder worldwide, characterized primarily by motor symptoms such as resting tremor, rigidity, and bradykinesia, accompanied by non-motor symptoms (NMS) including constipation and depression. The underlying mechanisms of PD are multifaceted, driven by a complex interaction between genetic and environmental factors that remain to be entirely understood. In recent years, an increasing body of evidence has confirmed that the abnormal aggregation of α-synuclein (α-Syn), mitochondrial dysfunction, and neuroinflammatory activation are not isolated pathological events; rather, they constitute the core driving mechanism of PD pathogenesis and progression through complex networked interactions. This narrative review examines the independent mechanisms of these three pathological components, provides an in-depth analysis of their regulatory interaction networks, and summarizes therapeutic targets and synergistic treatment strategies for the pathological axes, aiming to provide theoretical support for disease-modifying therapy and early intervention in PD.

Keywords:  Interaction; Mitochondrial dysfunction; Neuroinflammation; Parkinson’s disease; Therapeutic strategies; α-Synuclein

DOI:  https://doi.org/10.1007/s00415-026-13900-3
Chembiochem. 2026 Jun 15. 27(11): e70398

Lipid Dynamics in the Amyloid Cascade Hypothesis: Evaluating the Biological Relevance of In Vitro Models.

Sofia Serravalle, Fabio Lolicato, Carmelo Tempra, Martina Pannuzzo, Michele F M Sciacca, Danilo Milardi, Carmelo La Rosa.

  This review explores the role of misfolded protein aggregates in disrupting cell membranes, a key mechanism of cytotoxicity in proteinopathies. The lipid-chaperone hypothesis (LCH) suggests that the dynamic equilibrium between lipids and lipid vesicles, governed by critical micellar concentration, should be considered when linking protein misfolding and aggregation to membrane damage. Despite the success of LCH in model systems, observing these processes in living cells is challenging due to their complex environments, which can introduce confounding variables. To fill this gap, we examine various physiopathological factors that influence the concentration of free lipids in cellular aqueous solutions, including lipid chain length, oxidative modifications, enzyme-mediated degradation, and pathological lipid dysmetabolism, all while accounting for the accumulation of misfolded proteins which is related to the onset of the diseases. This comprehensive analysis aims to provide a unified framework for understanding the cascade of molecular events connecting protein misfolding, aggregation, membrane damage, and resultant cytotoxicity.

Keywords:  amyloid; biochemistry; cell biology; dynamic equilibrium; lipid signaling; membrane; membrane lipids; oxidative phosphorylation; protein aggregation; protein folding

DOI:  https://doi.org/10.1002/cbic.70398