bims-proned 2026-08-02 papers

Issue of 2026–08–02
four papers selected by
Verena Kohler, Umeå University

bioRxiv. 2026 Jul 23. pii: 2026.07.20.739556. [Epub ahead of print]

Leveraging Supramolecular Polymers to Induce the Targeted Protein Degradation of α-Synuclein.

Windfield S Swetman, Malay Mondal, Ashe M Davis, Vijay Rangachari, Tristan D Clemons.

Halting the progression of neurodegenerative diseases remains one of the foremost challenges in medicinal chemistry due to the complex biology that drives disease progression. For example, a hallmark of synucleinopathies, such as Parkinson's disease, is the misfolding and aggregation of the protein α-Synuclein (α-Syn), driving the formation of toxic oligomers and fibrils that avoid natural intracellular clearance mechanisms, participate in unusual protein-protein interactions, and ultimately contribute to the death of dopaminergic neurons. The field of targeted protein degradation (TPD) has emerged as an innovative therapeutic route to selectively degrade proteins of interest that leverage natural intracellular protein degradation machinery. First generation TPD therapeutics have traditionally been designed as bifunctional, chimeric compounds in which a short covalent linker tethers a ligand designed to bind target proteins to a ligand that initiates an either proteosome- or lysosome-dependent protein degradation cascade. While initial studies have indicated the promise of these approaches, translation to the clinical setting has been challenging due to difficulties in achieving cellular internalization, long-term stability, and establishment of a generalizable strategy. To overcome these obstacles, this work has focused on adding modularity and dynamic capability to this classical model by leveraging a multivalent macromolecular approach to TPD. Specifically, peptide amphiphiles (PAs) were designed to self-assemble into high-aspect-ratio supramolecular nanofibers and present peptide epitopes on the surface of the fibers to target simultaneous binding of α-Syn and recruitment of enzymes that facilitate entry into the lysosome-dependent chaperone-mediated autophagy protein degradation pathway. In vitro application of these bioactive PA nanofibers has demonstrated the ability to independently internalize in cells and reduce α-Syn protein levels selectively and effectively. While further optimization of this model has the potential to be a viable therapeutic against α-Syn aggregation, the modularity of these supramolecular nanofibers through facile monomer design and incorporation illustrates the potential of establishing a platform technology for targeting a diverse range of pathologic proteins.

DOI: https://doi.org/10.64898/2026.07.20.739556

Biomolecules. 2026 Jul 18. pii: 1053. [Epub ahead of print]16(7):

Shrinking of Extracellular Space During Metabolic Stress Accelerates Amyloid-β Aggregation.

Laura F De Oliveira, Kanchana Karunarathne, Dalton Zona, Martin Muschol, Ghanim Ullah.

Pathological states associated with metabolic stress, such as traumatic brain injury (TBI), hypoxia, ischemic stroke, and migraine, are considered elevated risk factors for developing Alzheimer's disease (AD). However, the mechanism underlying the effect of these conditions on the progression of AD remains largely unknown. Here, we determine how metabolic stress associated with spreading depolarization (SD)-a hallmark of stroke, hypoxia, TBI, and migraine-modulates amyloid β (Aβ42) aggregation kinetics through dynamic changes in extracellular space (ECS). To achieve this, we used ThT fluorescence to determine how the formation of different Aβ42 aggregate species depends on Aβ42 concentrations. Based on this input, we build a multiscale computational framework that integrates volume regulation, including its dependence on neuronal ion homeostasis, and Aβ42 aggregation kinetics. Our model predicts that neuronal swelling during SD accelerates aggregation, where the impact of metabolic stress is highly dependent on the timing relative to aggregation progression and the initial monomer concentration. At low monomer concentrations, early SD events promote off-pathway oligomer formation, while at higher concentrations they rapidly drive fibril formation to saturation. In the absence of mature fibrils, recurrent metabolic stress events further amplify oligomer accumulation, whereas pre-existing fibril nuclei suppress oligomer formation at the expense of fibril nucleation and growth. Increasing the intensity of metabolic stress prolongs ECS shrinkage and enhances oligomer formation. These findings reveal a mechanistic link between SD-induced microenvironmental changes and Aβ aggregation dynamics, providing a quantitative framework for understanding how acute brain injury and metabolic stress may contribute to early AD pathogenesis.

Keywords: Alzheimer’s disease; Amyloid β; aggregation; metablic stress; spreading depolarization

DOI: https://doi.org/10.3390/biom16071053

bioRxiv. 2026 Jul 14. pii: 2026.07.10.737840. [Epub ahead of print]

α-Synuclein pathology differentially alters T-type calcium currents in vulnerable and resilient substantia nigra dopaminergic subpopulations.

Megan L Beaver, Pallavi Bommareddy, Natalie Z McLean, Valerie J Lewitus, Kathleen Maguire-Zeiss, Rebekah C Evans.

Aggregation of α-synuclein protein is a characteristic of Parkinson's disease pathology that relates to the degeneration of vulnerable dopaminergic neurons and motor symptoms of the disease. However, α-synuclein pathology can contribute to neuronal dysfunction by disrupting several processes within the cell, including intracellular calcium balance, mitochondrial function, and synaptic function. Here, we use a preformed fibril (PFF) model of synucleinopathy to examine effects of striatal α-synuclein seeding on dopamine neurons of the substantia nigra pars compacta (SNc). The SNc is heterogeneous and contains dopaminergic neurons with differential vulnerability to Parkinson's disease pathology. We found that intrastriatal injections of PFFs differentially affect these SNc neuron subtypes by increasing the excitability of resilient SNc neurons, while altering tonic firing patterns and T-type calcium currents in vulnerable SNc neurons. In addition, we performed comprehensive electrophysiological analyses and neural morphology reconstructions on SNc neurons from PFF and monomer injected mice. These findings provide insights to the selective vulnerability of SNc neuron subtypes and further our understanding of the role of α-synuclein in Parkinson's disease progression and circuit dysfunction.

DOI: https://doi.org/10.64898/2026.07.10.737840

bioRxiv. 2026 Jul 14. pii: 2026.07.13.738277. [Epub ahead of print]

FAIM Inhibits Insulin Amyloidogenesis through a Noncanonical Aggregation Pathway.

Dana Wolfe, Jhinuk Saha, Joshua Mitchell, Sam McCalpin, Michael Gutknecht, Charles L Brooks, Thomas L Rothstein, Ayyalusamy Ramamoorthy.

Insulin can misfold and assemble into amyloid fibrils, a process linked not only to complications of insulin therapy but also to proteotoxic stress in pancreatic β-cells. Despite growing interest in the pathological consequences of insulin aggregation, prevention efforts are limited by an incomplete understanding of the endogenous mechanisms that counteract it. Here, we identify Fas apoptosis inhibitory molecule (FAIM) as an endogenous suppressor of insulin amyloid formation. FAIM reduces β-sheet formation and redirects insulin toward disordered, growth-incompetent assemblies. Further, FAIM attenuates the cytotoxicity of insulin aggregates in vitro . We hypothesize that this effect arises from masking aggregation-prone regions of insulin and show through structural modeling that FAIM interacts with both insulin chains. These findings extend the anti-aggregation function of FAIM to insulin and suggest a mechanism for endogenous suppression of insulin amyloid formation. More broadly, our results provide insight into the regulation of insulin assembly and highlight FAIM as a candidate modulator of proteostasis in metabolic disease.
Statement for a broader audience: Insulin can clump together into harmful aggregates, contributing to complications of insulin therapy and potentially damaging the insulin-producing cells of the pancreas. This study identifies the naturally occurring protein FAIM as a protective factor that inhibits the formation of these harmful aggregates and reduces their toxicity. These findings improve our understanding of how cells protect insulin from harmful aggregation and may open new avenues for developing therapies to combat diabetes-related protein aggregation.

DOI: https://doi.org/10.64898/2026.07.13.738277