Mechanistic Characterization of NABi as a Selective Inhibitor of SOD1G93A Aggregation: Structural Basis and Therapeutic Implications for ALS

The HDAC Inhibitor Butyrate Reduces SOD1 Aggregation and Improves Motor Function in C. elegans and Cellular Models of ALS

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterised by motor neuron loss and protein aggregation, commonly driven by mutations in superoxide dismutase 1 (Sod1). Recent evidence implicates gut microbiota–derived metabolites, such as butyrate, in modulating neurodegeneration, but the underlying mechanisms remain unclear. Here, we demonstrate that sodium butyrate (NaB), a histone deacetylase inhibitor and microbial metabolite, ameliorates ALS‐related phenotypes in C. elegans and mammalian cell models expressing mutant isoforms of Sod1 linked to ALS. NaB treatment prevented Sod1 aggregation and restored motor function and axonal integrity in transgenic worms overexpressing Sod1G85R. Mechanistically, NaB recapitulated the effects of the pan‐HDAC inhibitor trichostatin A, suggesting HDAC inhibition as key to reducing Sod1 aggregation and its downstream effects. Application of NaB or the HDAC inhibitor valproic acid also prevented aggregation of Sod1A4V, Sod1G85R or Sod1G37R in transfected human neuroblastoma cells. These findings support a conserved neuroprotective role for NaB and HDAC inhibitors via their antiaggregation activity. Our findings also verify C. elegans and neuroblastoma cell lines as excellent research tools to explore the mechanisms underlying the antiaggregation action of NaB and HDAC inhibitors, as well as their potential for future therapeutic development.

Development of an RNA aptamer as a therapeutic agent for synucleinopathies

The aggregation of α-synuclein (αSyn), a 140-mer protein, has been implicated in the pathogenesis of Parkinson’s disease, multiple system atrophy, and dementia with Lewy bodies. KTKEGV repeats (KR) of αSyn are key mediators of prion-like propagation and neurodegeneration. Despite the availability of symptomatic treatments, no current therapy effectively delays disease progression. Here we report a 77-nucleotide (nt) RNA aptamer (1R6) with potent affinity and selectivity for αSyn1-95 (KD = 18 nM) through in vitro selection. 1R6 significantly inhibited αSyn oligomerization and β-sheet-rich fibril assembly and promoted disaggregation of preformed fibrils. Additionally, 1R6 suppressed αSyn seeding, as determined by FRET-based cellular biosensor cell assay. Cellular studies revealed that 1R6 cotransfection completely prevented αSyn-induced cytotoxicity. To assess the protective effects of 1R6 in vivo, we used a Drosophila melanogaster model expressing human αSyn in neurons. Flies fed with 1R6 showed improved locomotor defects, reduced photoreceptor degeneration, and decreased αSyn levels in the head. Structural characterization through 1H-15N heteronuclear multiple quantum correlation nuclear magnetic resonance experiments demonstrated that 1R6 targets KR motifs, a finding further supported by in silico simulations. Our findings indicate that RNA aptamers, such as 1R6, may represent promising therapeutic candidates for synucleinopathies, thus opening new avenues in the treatment of these diseases.

BL-918 as a Novel Neuroprotective Agent Targeting SMP30 in Parkinson’s Disease: A Therapeutic Evaluation

Parkinson’s disease is the second most common progressive neurodegenerative disorder, marked by the degeneration of dopaminergic neurons in the substantia nigra, leading to motor and non-motor impairments. Its etiology involves environmental toxins (pesticides, heavy metals, air pollutants), genetic mutations (LRRK2, SNCA, PARK2, PINK1, PARK7), oxidative stress, and mitochondrial dysfunction. Recent therapeutic strategies focus on neuroprotective agents that target oxidative stress and protein aggregation. Senescence Marker Protein30 (SMP30), also known as regucalcin, is an aging-related protein critical for antioxidative defense, calcium homeostasis, and neuronal survival. This study explores the potential of BL-918, along with gluconolactone and five control drugs (levodopa, carbidopa, ropinirole, pramipexole, amantadine), to enhance mouse SMP30 (Protein Data Bank Identifier [PDB ID]: 4GN7) structural modulation using in silico approaches. Molecular docking (AutoDock Vina) revealed BL-918 had the highest binding affinity (–10.2 kcal/mol). Molecular dynamics (GROMACS) demonstrated structural stability of the SMP30-BL-918 complex over 100 ns, supported by root mean square deviation (RMSD), radius of gyration (Rg), root mean square fluctuation (RMSF), and solvent accessible surface area (SASA) analyses. Hydrogen bonding was initially strong but transient. SwissADME and ProTox 3.0 characterized BL-918 as a viable therapeutic lead, outlining key pharmacokinetic targets for future optimization. Protein Contact Atlas and STRING analysis identified key non-covalent and protein-protein interactions. Due to BL-918’s low inhibition constant ( K i = 3.33 × 10 – 8 M), which indicates a high binding affinity, and its ADMET profile, it is suggested that BL-918 could potentially modulate SMP30 at the functional protein level. These strong initial docking interactions, despite exhibiting a decline in hydrogen bonds during molecular dynamics simulations, may lead to downstream regulatory effects that could be associated with increased expression of the SMP-30 protein, pending experimental validation.

Seipin modulates Alzheimer’s disease pathogenesis by regulating ferroptosis through a glycine-mediated metabolic pathway

Inhibition of amyloid β aggregation by venetoclax: a computational and in vitro experimental approach

The aggregation of amyloid β-protein (Aβ) plays a key role in the pathological progression of Alzheimer's disease (AD). Given the current absence of effective therapeutic strategies, the drug repurposing approach provides novel insights into the treatment of AD. Venetoclax, a B-cell lymphoma 2 (BCL-2) inhibitor, has demonstrated remarkable efficacy in the treatment of hematological malignancies, characterized by well-defined pharmacokinetic properties and a favorable safety profile. However, its effects and molecular mechanisms in the treatment of AD remain unexplored. Here, we investigated the potential of venetoclax in the inhibition of Aβ aggregation and elucidated its underlying mechanism. The inhibitory effect of venetoclax on Aβ aggregation was assessed using thioflavin T (ThT) fluorescence assays, transmission electron microscopy (TEM), and circular dichroism (CD) spectroscopy. Cellular assays were performed to evaluate the neuroprotective effects of venetoclax against Aβ42-induced neurotoxicity and oxidative stress. Molecular dynamics (MD) simulations were conducted to explore the molecular interactions between venetoclax and Aβ42 peptides. Venetoclax significantly inhibited Aβ aggregation, reduced fibril formation, and decreased β-sheet content at molar ratios of 2 : 1 and 1 : 1 (Aβ : venetoclax). Cellular assays showed that venetoclax attenuated Aβ42-induced neurotoxicity and oxidative stress. MD simulations revealed that venetoclax stabilized Aβ peptides via hydrogen-bonding networks, increasing solvent accessibility and reducing hydrophobic interactions. Venetoclax inhibited Aβ aggregation and mitigated Aβ-induced neurotoxicity by stabilizing Aβ peptide dynamics. These findings support the potential of venetoclax as a repurposed therapeutic candidate for AD.

DFT analysis of gamma-secretase interactions with potential inhibitors: therapeutic for Alzheimer's disease.

Alzheimers disease (AD) is a progressive neurodegenerative disorder characterized by the accumulation of β-amyloid (Aβ) plaques and neurofibrillary tangles, leading to cognitive decline. The enzyme γ-secretase (γS) plays a central role in Aβ production and is therefore an important therapeutic target. In this study, interaction energies were evaluated using the Molecular Fragmentation with Conjugated Caps (MFCC) method combined with Density Functional Theory (DFT) calculations to investigate the interactions between γS and the inhibitors Semagacestat (SEM) and Avagacestat (AVA). The SEM-γS complex exhibited a more favorable total interaction energy, primarily driven by interactions with residues such as Ala431, Lys380, and Leu425. In contrast, the AVA-γS complex showed prominent interactions involving key residues, including Leu381, Leu425, and Leu432, which participate in substrate recognition and stabilization within the enzymes binding pocket. Overall, both ligands highlight the combined importance of hydrophobic and hydrophilic interactions in stabilizing the complexes. This study provides molecular-level insights into the interaction mechanisms of γ-secretase inhibitors, contributing to a better understanding of structure-energy relationships that are essential for the rational design of more selective and effective therapeutic agents for Alzheimers disease.